4-benzylamino-1-carboxylacyl-piperidine derivatives as CETP inhibitors

ABSTRACT

The present invention provides a compound of formula (I): 
                         
wherein the variants R1, R2, R3, R4, R5, R6, R7 are as defined herein, and wherein said compound is an inhibitor of CETP, and thus can be employed for the treatment of a disorder or disease mediated by CETP or responsive to the inhibition of CETP.

This application claims benefit under 35 U.S.C. §119(e) of U.S.Provisional Application No. 60/986,456, filed Nov. 5, 2007, the contentsof which is incorporated herein by reference in its entirety.

The present invention related to novel compound of formula (I):

wherein,

R1 is cycloalkyl, heterocyclyl, aryl, alkyl-O—C(O)—, alkanoyl, or alkyl,wherein each cycloalkyl, heterocyclyl, or aryl is optionally substitutedwith one to three substituents selected from alkyl, aryl, haloalkyl,hydroxy, halogen, nitro, carboxy, thiol, cyano, HSO3-, cycloalkyl,alkenyl, alkoxy, cycloalkoxy, alkenyloxy, alkyl-O—C(O)—, alkanoyl,carbamoyl, alkyl-S—, alkyl-SO—, alkyl-SO2-, amino, mono- ordi-substituted (alkyl, cycloalkyl, aryl and/or aryl-alkyl-) amino,H2N—SO2-, or heterocyclyl, and wherein each alkanoyl, alkyl-O—C(O)—,alkyl, alkoxy, or heterocyclyl is further optionally substituted withone to three substituents selected from hydroxy, alkyl, halogen, nitro,carboxy, thiol, cyano, HSO3-, cycloalkyl, alkenyl, alkoxy, cycloalkoxy,alkenyloxy, alkyl-O—C(O)—, alkanoyl, carbamoyl, alkyl-S—, alkyl-SO—,alkyl-SO2-, amino, mono- or di-substituted (alkyl, cycloalkyl, aryland/or aryl-alkyl-)amino, H2N—SO2-, or heterocyclyl;

R2 is alkyl, cycloalkyl, cycloalkyl-alkyl-, or alkoxy, wherein eachalkyl, cycloalkyl or alkoxy is optionally substituted with one to threesubstituents selected from alkyl, alkoxy or halogen;

R3 is HOC(O)—R9-C(O)— or HOC(O)—R9-O—C(O)—,

R9 is -alkyl-, -alkyl-cycloalkyl-, -heterocyclyl-, -alkyl-heterocyclyl-,-heterocyclyl-alkyl-, -alkyl-aryl-, -cycloalkyl-, -cycloalkyl-alkyl-,-aryl-, -aryl-alkyl- or -cycloalkyl-alkyl-; or, wherein each R9 isoptionally substituted with one to three substituents selected fromalkyl, hydroxy, halogen, nitro, carboxy, thiol, cyano, HSO3-,cycloalkyl, alkenyl, alkoxy, cycloalkoxy, alkenyloxy, alkyl-haloalkyl,carboxy, carboxyamide, acyl, alkanoyl, carbamimidoyl, alkyl-S—,alkyl-SO—, alkyl-SO2-, amino, H2N—SO2-, heterocyclyl;

R4 and R5 are independently hydrogen, alkyl, alkoxy, cycloalkyl, aryl,heteroaryl, aryl-alkyl-, cycloalkyl-alkyl-, oxo or heteroaryl-alkyl-,wherein each alkyl, cycloalkyl, aryl, heteroaryl, aryl-alkyl-,cycloalkyl-alkyl-, or heteroaryl-alkyl- is optionally substituted withone to three substituents selected from alkyl, hydroxy, halogen,haloalkyl, nitro, carboxy, thiol, cyano, HSO3-, cycloalkyl, alkenyl,alkoxy, cycloalkoxy, haloalkoxy, alkenyloxy, alkyl-O—C(O)—, alkanoyl,carbamimidoyl, alkyl-S—, alkyl-SO—, alkyl-SO2-, amino, mono- ordi-substituted (alkyl, cycloalkyl, aryl and/or aryl-alkyl-) amino,H2N—SO2-, or heterocyclyl; with the proviso that R4 and R5 cannot behydrogen simultaneously;

R6 and R7 are independently hydrogen, alkyl, haloalkyl, halogen, cyano,nitro, hydroxy, amino, dialkylamino, alkoxy, haloalkoxy; or

or a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.

The present invention also relates to a process for the preparation ofthese compounds, to the use of these compounds and to pharmaceuticalpreparations containing such a compound I in free form or in the form ofa pharmaceutically acceptable salt.

Extensive pharmacological investigations have shown that the compounds Iand their pharmaceutically acceptable salts, for example, havepronounced selectivity in inhibiting CETP (cholesteryl ester transferprotein). CETP is involved in the metabolism of any lipoprotein inliving organisms, and has a major role in the reverse cholesteroltransfer system. Namely, CETP has drawn attention as a mechanism forpreventing accumulation of cholesterol in peripheral cells andpreventing arteriosclerosis. In fact, with regard to HDL having animportant role in this reverse cholesterol transfer system, a number ofepidemiological researches have shown that a decrease in CE (cholesterylester) of HDL in blood is one of the risk factors of coronary arterydiseases. It has been also clarified that the CETP activity variesdepending on the animal species, wherein arteriosclerosis due tocholesterol-loading is hardly induced in animals with lower activity,and in reverse, easily induced in animals with higher activity, and thathyper-HDL-emia and hypo-LDL (low density lipoprotein)-emia are inducedin the case of CETP deficiency, thus rendering the development ofarteriosclerosis difficult, which in turn led to the recognition of thesignificance of blood HDL, as well as significance of CETP that mediatestransfer of CE in HDL into blood LDL. While many attempts have been madein recent years to develop a drug that inhibits such activity of CETP, acompound having a satisfactory activity has not been developed yet.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 20carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbonatoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl and the like. When an alkyl group includes one or moreunsaturated bonds, it can be referred to as an alkenyl (double bond) oran alkynyl (triple bond) group. If the alkyl group can be substituted,it is preferably substituted by 1, 2 or 3 substituents selected fromhydroxy, halogen, nitro, carboxy, thiol, cyano, HSO3-, cycloalkyl,alkenyl, alkoxy, cycloalkoxy, alkenyloxy, alkoxycarbonyl, carbamimidoyl,alkyl-S—, alkyl-SO—, alkyl-SO2-, amino, H2N—SO2-, alkanoyl, orheterocyclyl, more preferably selected from hydroxy, halogen, nitro,carboxy, thiol, cyano, alkoxy, or amino.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-20 carbon atoms in the ring portion. Preferably, thearyl is a (C6-C10) aryl. Non-limiting examples include phenyl, biphenyl,naphthyl or tetrahydronaphthyl, most preferably phenyl, each of whichmay optionally be substituted by 1-4 substituents, such as alkyl,haloalkyl such as trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy,alkyl-C(O)—O—, aryl-O—, heteroaryl-O—, amino, acyl, thiol, alkyl-S—,aryl-S—, nitro, cyano, carboxy, alkyl-O—C(O)—, carbamoyl, alkyl-S(O)—,sulfonyl, sulfonamido, heterocyclyl, alkenyl, haloalkoxy, cycloalkoxy,alkenyloxy, alkoxycarbonyl, alkyl-SO—, alkyl-SO2-, amino, mono- ordi-substituted (alkyl, cycloalkyl, aryl and/or aryl alkyl)amino orH2N—SO2.

Furthermore, the term “aryl” as used herein, refers to an aromaticsubstituent which can be a single aromatic ring, or multiple aromaticrings that are fused together, linked covalently, or linked to a commongroup such as a methylene or ethylene moiety. The common linking groupalso can be a carbonyl as in benzophenone or oxygen as in diphenyletheror nitrogen as in diphenylamine.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. Preferably, alkoxy groups have about 1-7, more preferablyabout 1-4 carbons.

As used herein, the term “acyl” refers to a group R—C(O)— of from 1 to10 carbon atoms of a straight, branched, or cyclic configuration or acombination thereof, attached to the parent structure through carbonylfunctionality. Such group can be saturated or unsaturated, and aliphaticor aromatic. Preferably, R in the acyl residue is alkyl, or alkoxy, oraryl, or heteroaryl. When R is alkyl then the moiety is referred to aalkanoyl. Also preferably, one or more carbons in the acyl residue maybe replaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples include butare not limited to, acetyl, benzoyl, propionyl, isobutyryl,t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl refers toacyl containing one to four carbons.

As used herein, the term “acylamino” refers to acyl-NH—, wherein “acyl”is defined herein. As used herein, the term “carbamoyl” refers toH₂NC(O)—, alkyl-NHC(O)—, (alkyl)₂NC(O)—, aryl-NHC(O)—,alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—, alkyl(heteroaryl)-NC(O)—,aryl-alkyl-NHC(O)—, alkyl(aryl-alkyl)-NC(O)— and the like.

As used herein, the term “sulfonyl” refers to R—SO₂—, wherein R ishydrogen, alkyl, aryl, hetereoaryl, aryl-alkyl, heteroaryl-alkyl,aryl-O—, heteroaryl-O—, alkoxy, aryloxy, cycloalkyl, or heterocyclyl.

As used herein, the term “sulfonamido” refers to alkyl-S(O)₂—NH—,aryl-S(O)₂—NH—, aryl-alkyl-S(O)₂—NH—, heteroaryl-S(O)₂—NH—,heteroaryl-alkyl-S(O)₂—NH—, alkyl-S(O)₂—N(alkyl)-, aryl-S(O)₂—N(alkyl)-, aryl-alkyl-S(O)₂—N(alkyl)-, heteroaryl-S(O)₂—N(alkyl)-,heteroaryl-alkyl-S(O)₂—N(alkyl)- and the like.

As used herein, the term “alkoxycarbonyl” or “alkyl-O—C(O)—” refers toalkoxy-C(O)—, wherein alkoxy is defined herein.

As used herein, the term “alkanoyl” refers to alkyl-C(O)—, wherein alkylis defined herein.

As used herein, the term “alkenyl” refers to a straight or branchedhydrocarbon group having 2 to 20 carbon atoms and that contains at leastone double bonds. The alkenyl groups preferably have about 2 to 8 carbonatoms.

As used herein, the term “alkenyloxy” refers to alkenyl-O—, whereinalkenyl is defined herein.

As used herein, the term “cycloalkoxy” refers to cycloalkyl-O—, whereincycloalkyl is defined herein.

As used herein, the term “heterocyclyl” or “heterocyclo” refers to anoptionally substituted, fully saturated or unsaturated, aromatic ornonaromatic cyclic group, e.g., which is a 4- to 7-membered monocyclic,7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system,which has at least one heteroatom in at least one carbon atom-containingring. Each ring of the heterocyclic group containing a heteroatom mayhave 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atomsand sulfur atoms, where the nitrogen and sulfur heteroatoms may alsooptionally be oxidized. The heterocyclic group may be attached at aheteroatom or a carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, piperazinyl, piperidinyl,4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, 1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl andthe like.

Exemplary bicyclic heterocyclic groups include indolyl, dihydroidolyl,benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl,benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl,decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, 1,3-dioxo-1,3-dihydroisoindol-2-yl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),phthalazinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl,dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl,acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl,carbolinyl and the like.

When heterocyclyl is aromatic, this moiety is referred to as“heteroaryl”.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or fused polycyclic-ring system, having 1 to 8heteroatoms selected from N, O or S. Preferably, the heteroaryl is a5-10 membered ring system. Typical heteroaryl groups include 2- or3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-,4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl,2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl,4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or5-pyrimidinyl.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more aryl, cycloaliphatic, or heterocyclylrings, where the radical or point of attachment is on the heteroaromaticring. Nonlimiting examples include but are not limited to 1-, 2-, 3-,5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-,3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-,4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-,6-, 7-, or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-,3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl,3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-,2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-2-, 3-, 4-, 5-, 6-, 7-,or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-,3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-,7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-8-, or 9-perimidinyl, 2-,3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-, 3-, 4-, 6-, 7-,8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl,2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-,6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-,or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl,2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl,1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-,8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-,or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-,4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-,or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroaryl groupsinclude, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl.

A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic.

The term “heterocyclyl” further refers to heterocyclic groups as definedherein substituted with 1, 2 or 3 substituents selected from the groupsconsisting of the following: alkyl; haloalkyl, hydroxy (or protectedhydroxy); halo; oxo, i.e., ═O; amino, mono- or di-substituted (alkyl,cycloalkyl, aryl and/or aryl alkyl)amino such as alkylamino ordialkylamino; alkoxy; cycloalkyl; alkenyl; carboxy; heterocyclooxy,wherein heterocyclooxy denotes a heterocyclic group bonded through anoxygen bridge; alkyl-O—C(O)—; mercapto; HSO3; nitro; cyano; sulfamoyl orsulfonamido; aryl; alkyl-C(O)—O—; aryl-C(O)—O—; aryl-S—; cycloalkoxy;alkenyloxy; alkoxycarbonyl; aryloxy; carbamoyl; alkyl-S—; alkyl-SO—,alkyl-SO2-; formyl, i.e., HC(O)—; aryl-alkyl—; acyl such as alkanoyl;heterocyclyl and aryl substituted with alkyl, cycloalkyl, alkoxy,hydroxy, amino, alkyl-C(O)—NH—, alkylamino, dialkylamino or halogen.

As used herein, the term “cycloalkyl” refers to optionally substitutedsaturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbongroups of 3-12 carbon atoms, each of which may be substituted by one ormore substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl,acylamino, carbamoyl, alkyl-NH—, (alkyl)₂N—, thiol, alkylthio, nitro,cyano, carboxy, alkyl-O—C(O)—, sulfonyl, sulfonamido, sulfamoyl,heterocyclyl and the like. Exemplary monocyclic hydrocarbon groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl and cyclohexenyl and the like. Exemplarybicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl,tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like.

As used herein, the term “sulfamoyl” refers to H2NS(O)₂—,alkyl-NHS(O)₂—, (alkyl)₂NS(O)₂—, aryl-NHS(O)₂—, alkyl(aryl)-NS(O)₂—,(aryl)₂NS(O)₂—, heteroaryl-NHS(O)₂—, aryl-alkyl-NHS(O)₂—,heteroaryl-alkyl-NHS(O)₂— and the like.

As used herein, the term “aryloxy” refers to both an —O-aryl and an —O—heteroaryl group, wherein aryl and heteroaryl are defined herein.

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo, and iodo.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein, that is substituted by one or more halo groups as definedherein. Preferably the haloalkyl can be monohaloalkyl, dihaloalkyl orpolyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo,bromo, chloro or fluoro within the alkyl group. Dihaloalky andpolyhaloalkyl groups can have two or more of the same halo atoms or acombination of different halo groups within the alkyl. Preferably, thepolyhaloalkyl contains up to 12, 10, or 8, or 6, or 4, or 3, or 2 halogroups. Non-limiting examples of haloalkyl include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refersto an alkyl having all hydrogen atoms replaced with halo atoms.

As used herein, the term “dialkylamino” refers to an to an amino groupwhich is di-substituted by alkyl, whereby the alkyl can be the same ordifferent, as defined herein. Preferably the dialkylamino can have thesame alkyl substitutent. Non-limiting examples of dialkylamino includedimethylamino, diethylamino and diisopropylamino.

As used herein, the term “aryl alkyl” is interchangeable for“aryl-alkyl-”, wherein aryl and alkyl are defined herein.

As used herein, the term “cycloalkyl-alkyl-” is interchangeable for“cycloalkyl alkyl”, wherein cycloalkyl and alkyl are defined herein.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula. Also as used herein, the term “anoptical isomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric formsthat may be defined, in terms of absolute stereochemistry, as (R)- or(S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the biological effectiveness and properties of thecompounds of this invention and, which are not biologically or otherwiseundesirable. Non-limiting examples of the salts include non-toxic,inorganic and organic base or acid addition salts of compounds of thepresent invention. In many cases, the compounds of the present inventionare capable of forming acid and/or base salts by virtue of the presenceof amino and/or carboxyl groups or groups similar thereto.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acidsfrom which salts can be derived include, for example, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike. Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum, and thelike; particularly preferred are the ammonium, potassium, sodium,calcium and magnesium salts. Organic bases from which salts can bederived include, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, basic ion exchange resins, and the like, specificallysuch as isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. The pharmaceutically acceptable saltsof the present invention can be synthesized from a parent compound, abasic or acidic moiety, by conventional chemical methods. Generally,such salts can be prepared by reacting free acid forms of thesecompounds with a stoichiometric amount of the appropriate base (such asNa, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or byreacting free base forms of these compounds with a stoichiometric amountof the appropriate acid. Such reactions are typically carried out inwater or in an organic solvent, or in a mixture of the two. Generally,non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred, where practicable. Lists of additionalsuitable salts can be found, e.g., in Remington's PharmaceuticalSciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), whichis herein incorporated by reference.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289-1329, incorporated herein by reference). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.

The term “therapeutically effective amount” of a compound of the presentinvention refers to an amount of the compound of the present inventionthat will elicit the biological or medical response of a subject, orameliorate symptoms, slow or delay disease progression, or prevent adisease, etc. In a preferred embodiment, the “effective amount” refersto the amount that inhibits or reduces expression or activity of CETP.

As used herein, the term “subject” refers to an animal. Preferably, theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In a preferred embodiment, the subjectis a human.

As used herein, the term “a disorder” or “a disease” refers to anyderangement or abnormality of function; a morbid physical or mentalstate. See Dorland's Illustrated Medical Dictionary, (W.B. Saunders Co.27th ed. 1988).

As used herein, the term “inhibition” or “inhibiting” refers to thereduction or suppression of a given condition, symptom, or disorder, ordisease, or a significant decrease in the baseline activity of abiological activity or process. Preferably, the condition or symptom ordisorder or disease is mediated by CETP activity or responsive to theinhibition of CETP.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers in one embodiment, to ameliorating the disease ordisorder (i.e., arresting or reducing the development of the disease orat least one of the clinical symptoms thereof). In another embodiment“treating” or “treatment” refers to ameliorating at least one physicalparameter, which may not be discernible by the patient. In yet anotherembodiment, “treating” or “treatment” refers to modulating the diseaseor disorder, either physically, (e.g., stabilization of a discerniblesymptom), physiologically, (e.g., stabilization of a physicalparameter), or both. In yet another embodiment, “treating” or“treatment” refers to preventing or delaying the onset or development orprogression of the disease or disorder.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

The following preferred embodiments of the moieties and symbols informula I can be employed independently of each other to replace moregeneral definitions and thus to define specially preferred embodimentsof the invention, where the remaining definitions can be kept broad asdefined in embodiments of the inventions defined above of below.

In one embodiment, the invention is related to a compound of formula Iwherein

R1 is heterocyclyl, aryl, alkoxycarbonyl, alkanoyl, or alkyl, whereineach heterocyclyl or aryl is optionally substituted with one to threesubstituents selected from alkyl, haloalkyl, hydroxy, halogen, nitro,carboxy, thiol, cyano, HSO3-, cycloalkyl, alkenyl, alkoxy, cycloalkoxy,alkenyloxy, alkoxycarbonyl, carbamoyl, alkyl-S—, alkyl-SO—, alkyl-SO2-,amino, H2N—SO2-, alkanoyl, or heterocyclyl; and wherein each alkanoyl,alkoxycarbonyl, or alkyl is optionally substituted with one to threesubstituents selected from hydroxy, halogen, nitro, carboxy, thiol,cyano, HSO3-, cycloalkyl, alkenyl, alkoxy, cycloalkoxy, alkenyloxy,alkoxycarbonyl, carbamoyl, alkyl-S—, alkyl-SO—, alkyl-SO2-, amino,H2N—SO2-, alkanoyl, or heterocyclyl;R2 is alkyl;R3 is HO(O)C—R9-C(O)— or HO(O)C—R9-O—C(O)—,R9 is -alkyl-, -alkyl-cycloalkyl-, -heterocyclyl-, -alkyl-heterocyclyl-,-heterocyclyl-alkyl-, -alkyl-aryl-, -cycloalkyl-, -cycloalkyl-alkyl-,-aryl-, -aryl-alkyl- or -cycloalkyl-alkyl-; or, wherein each R9 isoptionally substituted with one to three substituents selected fromalkyl, hydroxy, halogen, nitro, carboxy, thiol, cyano, HSO3-,cycloalkyl, alkenyl, alkoxy, cycloalkoxy, alkenyloxy, alkyl-haloalkyl,carboxy, carboxyamide, acyl, alkanoyl, carbamimidoyl, alkyl-S—,alkyl-SO—, alkyl-SO2-, amino, H2N—SO2-, heterocyclyl;R4 or R5 are independently of each other hydrogen, alkyl, aryl-alkyl-,cycloalkyl-alkyl- or heteroaryl-alkyl-, wherein each aryl, cycloalkyl orheteroary is optionally substituted with one to three substituentsselected from alkyl, haloalkyl, hydroxy, halogen, nitro, carboxy, thiol,cyano, HSO3-, cycloalkyl, alkenyl, alkoxy, haloalkoxy, cycloalkoxy,alkenyloxy, alkoxycarbonyl, alkyl-S—, alkyl-SO—, alkyl-SO2-, amino,mono- or di-substituted (alkyl, cycloalkyl, aryl and/or aryl-alkyl-)amino; H2N—SO2-, or alkanoyl;R6 and R7 are independently hydrogen, alkyl, haloalkyl, halogen, cyano,nitro, hydroxy, dialkylamino or alkoxy; orR6 is aryl or heteroaryl; ora pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.Preferred Definitions for R1

Preferably, R1 is heterocyclyl, aryl, alkoxycarbonyl, alkanoyl, oralkyl, wherein each heterocyclyl or aryl is optionally substituted withone to three substituents selected from alkyl, haloalkyl, hydroxy,halogen, nitro, carboxy, thiol, cyano, HSO3-, cycloalkyl, alkenyl,alkoxy, cycloalkoxy, alkenyloxy, alkoxycarbonyl, carbamoyl, alkyl-S—,alkyl-SO—, alkyl-SO2-, amino, H2N—SO2-, alkanoyl, or heterocyclyl; andwherein each alkanoyl, alkoxycarbonyl, or alkyl is optionallysubstituted with one to three substituents selected from hydroxy,halogen, nitro, carboxy, thiol, cyano, HSO3-, cycloalkyl, alkenyl,alkoxy, cycloalkoxy, alkenyloxy, alkoxycarbonyl, carbamoyl, alkyl-S—,alkyl-SO—, alkyl-SO2-, amino, H2N—SO2-, alkanoyl, or heterocyclyl. Morepreferably, R1 is cycloalkyl, heterocyclyl, heteroaryl, alkanoyl oralkoxycarbonyl, wherein each heterocyclyl is optionally substituted withone to three substituents selected from alkyl, hydroxy, halogen, nitro,carboxy, thiol, cyano, HSO3-, cycloalkyl, alkenyl, alkoxy, cycloalkoxy,alkenyloxy, alkoxycarbonyl, carbamoyl, alkyl-S—, alkyl-SO—, alkyl-SO2-,amino, H2N—SO2-, alkanoyl, or heterocyclyl, more preferably alkyl,hydroxy, halogen, carboxy, alkoxy, amino, alkanoyl or heterocyclyl.Preferred examples for the heterocyclyl substituent of the heterocyclylmoiety for R1 is a 5- to 6-membered, preferably fully saturated ringcontaining at least one heteroatom selected from O, N or S, morepreferably N, most preferably it is morpholinyl.

A preferred meaning of variable R1 is heteroaryl as preferablyrepresented by formulae

or pyridyl, especially which are each unsubstituted or substituted byC1-C4-alkyl, especially methyl or halo, aryl, heterocyclyl orheteroaryl. A preferred substituent for

is morpholinyl, or pyrazole which is unsubstituted or substituted byC1-C4-alkyl.Preferred Definitions for R2

Preferably, R2 is straight chain or branched C1-C6 alkyl as definedherein. Examples include methyl, ethyl, isopropyl, n-propyl, isobutyl,n-butyl or sec-butyl, more preferably ethyl or isobutyl, most preferablyethyl.

Preferred Definitions for R3

Preferably R3 is HO(O)C—R9-C(O)— or HO(O)C—R9-O—C(O)—.

Preferred Definitions for R9

Preferably R9 is -alkyl-, -alkyl-cycloalkyl-, -heterocyclyl-,-alkyl-heterocyclyl-, -heterocyclyl-alkyl-, -alkyl-aryl-, -cycloalkyl-,-cycloalkyl-alkyl-, -aryl-, -aryl-alkyl- or -cycloalkyl-alkyl-; or,wherein each R9 is optionally substituted with one to three substituentsselected from alkyl, hydroxy, halogen, nitro, carboxy, thiol, cyano,HSO3-, cycloalkyl, alkenyl, alkoxy, cycloalkoxy, alkenyloxy,alkyl-haloalkyl, carboxy, carboxyamide, acyl, alkanoyl, carbamimidoyl,alkyl-S—, alkyl-SO—, alkyl-SO2-, amino, H2N—SO2-, heterocyclyl;

Most preferable is C₂₋₅alkyl, C₄₋₆cycloalkyl, —CH₂—C₄₋₆cycloalkyl,C₄₋₆cycloalkyl-CH₂—, C₅₋₆ aryl, C₄₋₆ heterocyclyl or C₅₋₆ heteroaryl.Most preferred are

CH2C(CH3)2CH2CH2-,

Preferred Definitions for R4 and R5

Preferably R4 or R5 are independently of each other hydrogen, alkyl,cycloalkyl, aryl, heteroaryl, aryl-alkyl-, cycloalkyl-alkyl- orheteroaryl-alkyl-, more preferably hydrogen, aryl-alkyl-,cycloalkyl-alkyl- or heteroaryl-alkyl-, wherein each alkyl, isoptionally substituted with one to three substituents selected fromhydroxy, halogen, nitro, carboxy, thiol, cyano, HSO3-, cycloalkyl,alkenyl, alkoxy, haloalkoxy, cycloalkoxy, alkenyloxy, alkoxycarbonyl,alkyl-S—, alkyl-SO—, alkyl-SO2-, amino, mono- or di-substituted (alkyl,cycloalkyl, aryl and/or aryl-alkyl-) amino; H2N—SO2-, or alkanoyl, andwherein each aryl, cycloalkyl or heteroaryl is optionally substitutedwith one to three substituents selected from alkyl, haloalkyl, hydroxy,halogen, nitro, carboxy, thiol, cyano, HSO3-, cycloalkyl, alkenyl,alkoxy, haloalkoxy, cycloalkoxy, alkenyloxy, alkoxycarbonyl, alkyl-S—,alkyl-SO—, alkyl-SO2-, amino, mono- or di-substituted (alkyl,cycloalkyl, aryl and/or aryl-alkyl-) amino; H2N—SO2-, or alkanoyl.

More preferably R4 or R5 are independently of each other hydrogen,benzyl, or cycloalkyl-CH2-, wherein each benzyl or cycloalkyl isoptionally substituted with one to three substituents selected fromalkyl, haloalkyl, hydroxy, halogen, nitro, carboxy, thiol, cyano, HSO3-,alkoxy, haloalkoxy, amino, mono- or di-substituted (alkyl, cycloalkyl,aryl and/or aryl-alkyl-) amino; H2N—SO2-, or alkanoyl.

In one embodiment, one of R4 and R5, preferably R5, is hydrogen and theother, preferably R4, is a group as defined herein other than hydrogen.

In another embodiment, both R4 and R5 are hydrogen.

Most preferably, R4 is ethyl or benzyl. It is also preferred that inthis case R5 is hydrogen.

Preferred Definitions for R6 and R7

Preferably, R6 and R7 are independently hydrogen, alkyl, haloalkyl,halogen, or alkoxy.

More preferably, R6 and R7 are independently hydrogen, alkyl orhaloalkyl, such as trifluoromethyl.

In one embodiment, one of R6 and R7 is hydrogen and the other is a groupas defined herein other than hydrogen.

In another preferred embodiment, both R6 and R7 are the same and are asdefined herein, most preferably trifluoromethyl.

The positions of R6 and R7 on the phenyl ring are preferably as follows:

Any asymmetric carbon atom on the compounds of the present invention canbe present in the (R)-, (S)- or (R,S)-configuration, preferably in the(R)- or (S)-configuration. Substituents at atoms with unsaturated bondsmay, if possible, be present in cis-(Z)- or trans-(E)-form. Therefore,the compounds of the present invention can be in the form of one of thepossible isomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Preferred isomers of the compound of the present invention can berepresented by the following formula:

in particular:

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure geometricor optical isomers, diastereomers, racemates, for example, bychromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, the imidazolyl moiety may thusbe employed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Finally, compounds of the present invention are either obtained in thefree form, as a salt thereof, or as prodrug derivatives thereof.

When a basic group is present in the compounds of the present invention,the compounds can be converted into acid addition salts thereof, inparticular, acid addition salts with the imidazolyl moiety of thestructure, preferably pharmaceutically acceptable salts thereof. Theseare formed, with inorganic acids or organic acids. Suitable inorganicacids include but are not limited to, hydrochloric acid, sulfuric acid,a phosphoric or hydrohalic acid. Suitable organic acids include but arenot limited to, carboxylic acids, such as (C1-C4)alkanecarboxylic acidswhich, for example, are unsubstituted or substituted by halogen, e.g.,acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g.,oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylicacids, e.g., glycolic, lactic, malic, tartaric or citric acid, such asamino acids, e.g., aspartic or glutamic acid, organic sulfonic acids,such as (C1-C4)alkylsulfonic acids, e.g., methanesulfonic acid; orarylsulfonic acids which are unsubstituted or substituted, e.g., byhalogen. Preferred are salts formed with hydrochloric acid,methanesulfonic acid and maleic acid.

When an acidic group is present in the compounds of the presentinvention, the compounds can be converted into salts withpharmaceutically acceptable bases. Such salts include alkali metalsalts, like sodium, lithium and potassium salts; alkaline earth metalsalts, like calcium and magnesium salts; ammonium salts with organicbases, e.g., trimethylamine salts, diethylamine salts,tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts andN-methyl-D-glucamine salts; salts with amino acids like arginine, lysineand the like. Salts may be formed using conventional methods,advantageously in the presence of an ethereal or alcoholic solvent, suchas a lower alkanol. From the solutions of the latter, the salts may beprecipitated with ethers, e.g., diethyl ether. Resulting salts may beconverted into the free compounds by treatment with acids. These orother salts can also be used for purification of the compounds obtained.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention can also form internalsalts.

The present invention also provides pro-drugs of the compounds of thepresent invention that converts in vivo to the compounds of the presentinvention. A pro-drug is an active or inactive compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject. The suitability andtechniques involved in making and using pro-drugs are well known bythose skilled in the art. Prodrugs can be conceptually divided into twonon-exclusive categories, bioprecursor prodrugs and carrier prodrugs.See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth,Academic Press, San Diego, Calif., 2001). Generally, bioprecursorprodrugs are compounds are inactive or have low activity compared to thecorresponding active drug compound, that contains one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollow types:

1. Oxidative reactions, such as oxidation of alcohol, carbonyl, and acidfunctions, hydroxylation of aliphatic carbons, hydroxylation ofalicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation ofcarbon-carbon double bonds, oxidation of nitrogen-containing functionalgroups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-delakylation, oxidative O- and S-delakylation, oxidative deamination,as well as other oxidative reactions.2. Reductive reactions, such as reduction of carbonyl groups, reductionof alcoholic groups and carbon-carbon double bonds, reduction ofnitrogen-containing functions groups, and other reduction reactions.3. Reactions without change in the state of oxidation, such ashydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogensingle bonds, hydrolytic cleavage of non-aromatic heterocycles,hydration and dehydration at multiple bonds, new atomic linkagesresulting from dehydration reactions, hydrolytic dehalogenation, removalof hydrogen halide molecule, and other such reactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. See, Cheng et al., US20040077595,application Ser. No. 10/656,838, incorporated herein by reference. Suchcarrier prodrugs are often advantageous for orally administered drugs.Carrier prodrugs can, for example, be used to improve one or more of thefollowing properties: increased lipophilicity, increased duration ofpharmacological effects, increased site-specificity, decreased toxicityand adverse reactions, and/or improvement in drug formulation (e.g.,stability, water solubility, suppression of an undesirable organolepticor physiochemical property). For example, lipophilicity can be increasedby esterification of hydroxy groups with lipophilic carboxylic acids, orof carboxylic acid groups with alcohols, e.g., aliphatic alcohols.Wermuth, The Practice of Medicinal Chemistry, Ch. 31-32, Ed. Werriuth,Academic Press, San Diego, Calif., 2001.

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyland O-acyl derivatives of thiols, alcohols or phenols, wherein acyl hasa meaning as defined herein. Preferred are pharmaceutically acceptableester derivatives convertible by solvolysis under physiologicalconditions to the parent carboxylic acid, e.g., lower alkyl esters,cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- ordi-substituted lower alkyl esters, such as the ω-(amino, mono- ordi-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters,the α-(lower alkanoyloxy, lower alkoxycarbonyl or di-loweralkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethylester and the like conventionally used in the art. In addition, amineshave been masked as arylcarbonyloxymethyl substituted derivatives whichare cleaved by esterases in vivo releasing the free drug andformaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugscontaining an acidic NH group, such as imidazole, imide, indole and thelike, have been masked with N-acyloxymethyl groups (Bundgaard, Design ofProdrugs, Elsevier (1985)). Hydroxy groups have been masked as estersand ethers. EP 039,051 (Sloan and Little) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use.

In view of the close relationship between the compounds, the compoundsin the form of their salts and the pro-drugs, any reference to thecompounds of the present invention is to be understood as referring alsoto the corresponding pro-drugs of the compounds of the presentinvention, as appropriate and expedient.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization.

The compounds of the present invention have valuable pharmacologicalproperties. The compounds of the present invention are useful asinhibitors for cholesteryl ester transfer protein (CETP). CETP is a 74KD glycopeptide, it is secreted by the liver and is a key player infacilitating the transfer of lipids between the various lipoproteins inplasma. The primary function of CETP is to redistribute cholesterylesters (CE) and triglycerides between lipoproteins. See Assmann, G etal., “HDL cholesterol and protective factors in atherosclerosis,”Circulation, 109: 1118-1114 (2004). Because most triglycerides in plasmaoriginate in VLDLs and most CEs are formed in HDL particles in thereaction catalyzed by lecithin:cholesterol acyltransferase, activity ofCETP results in a net mass transfer of triglycerides from VLDLs to LDLsand HDLs and a net mass transfer of CEs from HDLs to VLDLs and LDLs.Thus, CETP potentially decreases HDL-C levels, increases LDL-cholesteryl(LDL-C) levels and reduces HDL and LDL particles size, and inhibition ofCETP could be a therapeutic strategy for raising HDL-cholesteryl(HDL-C), have a favorable impact on the lipoprotein profile, and reducethe risk of cardiovascular diseases. Accordingly, the compounds of thepresent invention as CETP inhibitors are useful for the delay ofprogression and/or treatment of a disorder or disease that is mediatedby CETP or responsive to inhibition of CETP. Disorders, conditions anddiseases that can be treated with the compounds of the present inventioninclude but are not limited to, hyperlipidemia, arteriosclerosis,atherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, cardiovascular disorder, coronary heart disease,coronary artery disease, coronary vascular disease, angina, ischemia,heart ischemia, thrombosis, cardiac infarction such as myocardialinfarction, stroke, peripheral vascular disease, reperfusion injury,angioplasty restenosis, hypertension, congestive heart failure, diabetessuch as type II diabetes mellitus, diabetic vascular complications,obesity, infection or egg embryonation of schistosoma, or endotoxemiaetc.

Additionally, the present invention provides:

-   -   a compound of the present invention as described herein above        for use as a medicament;    -   the use of a compound of the present invention as described        herein above for the preparation of a pharmaceutical composition        for the delay of progression and/or treatment of a disorder or        disease mediated by CETP, or responsive to inhibition of CETP.    -   the use of a compound of the present invention as described        herein above for the preparation of a pharmaceutical composition        for the delay of progression and/or treatment of a disorder or        disease selected from hyperlipidemia, arteriosclerosis,        atherosclerosis, peripheral vascular disease, dyslipidemia,        hyperbetalipoproteinemia, hypoalphalipoproteinemia,        hypercholesterolemia, hypertriglyceridemia, familial        hypercholesterolemia, cardiovascular disorder, coronary heart        disease, coronary artery disease, coronary vascular disease,        angina, ischemia, heart ischemia, thrombosis, cardiac infarction        such as myocardial infarction, stroke, peripheral vascular        disease, reperfusion injury, angioplasty restenosis,        hypertension, congestive heart failure, diabetes such as type II        diabetes mellitus, diabetic vascular complications, obesity or        endotoxemia etc.

The compounds of formula (I) can be prepared by the procedures describedin the following sections.

Generally, the compounds of formula (I) can be prepared according to thefollowing general procedures and schemes. In all these Schemes thevariants R1, R2, R3, R4, R5, R6, R7 and R8 have the meaning as set forthherein unless defined otherwise.

1. General Procedure A: Using Piperidinone A1

Route AI when R4 and R5 are hydrogen:

-   -   a-1: ClCO₂R8; then R₂Mx, or    -   a-2: ClCO₂Ph; then R₂Mx; then KOR8, or    -   a-3: For R8=t-Bu, a-2 or Boc₂O; then R2Mx        wherein R8 is as defined herein e.g. t-Bu, Bn,        2,2,2-trichloroethyl, allyl, Mx is e.g. MgBr, MgI, MgCl, Li,        also combination with ZnCl2.

In step b) standard conditions for 1,4-reductions may be employed, suchas Mg, alcohol; CeCl3, NaBH4, or catalytic hydrogenation.

Route AII when R4 and R5 are hydrogen:

-   -   a-1: ClCO₂R8; then hydride agent, or    -   a-2: ClCO₂Ph; then hydride agent; then KOR8, or    -   a-3: For R8=t-Bu, a-2 or Boc₂O; then hydride agent        wherein R8 is as defined herein e.g. t-Bu, Bn,        2,2,2-trichloroethyl, allyl. Suitable hydride agents that can be        used are such as NaBH(OAc)₃, NaBH(CN)₃, NaBH4, or LiBH4,        K(OiPr)BH NaB[CH(CH)CH]H, or NaAlH(OCHCHOCH).

In step b) standard conditions for 1,4-additions are employed such asR2MgX (X=halo), CuI or R22Zn, cat. Cu species.

Route AIII when R5 is hydrogen:

-   -   a-1: CICO₂R8; then R₂Mx, or    -   a-2: CICO₂Ph; then R₂Mx; then KOR8, or    -   a-3: For R8=t-Bu, a-2 or Boc₂O; then R2Mx        wherein R₈ is as defined herein e.g. t-Bu, Bn,        2,2,2-trichloroethyl, allyl, Mx is e.g. MgBr, MgI, MgCl, Li,        also combination with ZnCl2.

In step b) standard conditions for 1,4-additions are employed such asR4MgX (X=halo), CuI or R42Zn, cat. Cu species.

Route AIV when R5 is hydrogen:

-   -   a-1: ClCO₂R8; then R4Mx, or    -   a-2: ClCO₂Ph; then R4Mx; then KOR8, or    -   a-3: For R8=t-Bu, a-2 or Boc₂O; then R4Mx        wherein R8 is as defined herein e.g. t-Bu, Bn,        2,2,2-trichloroethyl, allyl, Mx is e.g. MgBr, MgI, MgCl, Li,        also combination with ZnCl2.

In step b) standard conditions for 1,4-additions are employed such asR2MgX (X=halo), CuI or R22Zn, cat. Cu species.

Route AV when R4 is Hydrogen:

-   -   a-1: ClCO₂R8; then hydride agent, or

a-2: ClCO₂Ph; then hydride agent; then KOR8, or

a-3: For R₈=t-Bu, a-2 or Boc₂O; then hydride agent d

wherein R8 is as defined herein. Suitable hydride agents that can beused are such as NaBH(OAc)3, NaBH(CN)3, NaBH4, or LiBH4, K(OiPr)BHNaB[CH(CH)CH]H, or NaAlH(OCHCHOCH).

In step b) standard conditions for alkylations are employed, such asstrong base and a halide LDA, R5X or LHMDS or KHMDS, R5X (X=halogen orOMs, OTs, OTf).

In step c) standard conditions for 1,4-additions are employed such asR2MgX (X=halo), CuI or R22Zn, cat. Cu species.

Conversion of R3 can be effected by standard functional groupmanipulation as well known in the art or as specifically describedherein.

Route AVI when R4 is Hydrogen:

-   -   a-1: ClCO₂R8; then R2Mx, or    -   a-2: ClCO₂Ph; then R2Mx; then KOR8, or    -   a-3: For R8=t-Bu, a-2 or BOC₂O; then R2Mx        wherein R8 and R3 are as defined herein; Mx is e.g. MgBr, MgI,        MgCl, Li, also combination with ZnCl2.

In step b) the conversion of R3 can be effected by standard functionalgroup manipulation as well known in the art or as specifically describedherein.

In step c) standard conditions for enamine alkylations are employed,such as R5X (X=halogen or OMs, OTs, OTf); heat; or 12 and the use of abase to form a vinyl iodide followed by cross-coupling conditions suchas Suzuki, Stille, Negishi or Kumada as described e.g. in standardtextbooks.

In step d) standard conditions for 1,4-reductions may be employed, suchas Mg, alcohol; CeCl3, NaBH4, or catalytic hydrogenation.

Route AVII:

a-1: ClCO₂R8; then R4Mx, ora-2: ClCO₂Ph; then R4Mx; then KOR8, ora-3: For R8=t-Bu, a-2 or Boc₂O; then R4Mxwherein R8 and R3 are as defined herein; Mx is e.g. MgBr, MgI, MgCl, Li,also combination with ZnCl2.

In step b) standard conditions for alkylations are employed, such asstrong base and a halide; e.g. LDA, R4X or LHMDS or KHMDS, R4X(X=halogen or OMs, OTs, OTf).

In step c) standard conditions for 1,4-additions are employed such asR5MgX (X=halo), CuI or R52Zn, cat. Cu species.

In step d) the conversion of R3 can be effected by standard functionalgroup manipulation as well known in the art or as specifically describedherein.

Using any of the routes AI to AVII above, the piperidone A1 can beconverted into the compound of formula (I) using one of the routesAVIII, AIX or AX shown below.

Route AVIII:

In step a) standard methods for reductive amination are employed, suchas ArCH2NH2, hydride reagent [ex. NaBH(OAc)3, NaBH(CN)3, NaBH4, LiBH4,BH3, picoline borane, borane-pyridine complex]; or Ti(OiPr)4; thenhydride reagent such as NaBH(OAc)3, NaBH(CN)3, NaBH4, LiBH4, borane,picoline borane, borane-pyridine complex, LiAlH4, 9-BBN, Alpine boraneR®, LiB(s-Bu)3H, LiB(Sia)3H; or imine formation catalyzed or uncatalyzedby acid followed by reduction by hydride agents (see above).

In step b), group R1 is introduced by usual functional groupmanipulation in the amine, such as alkylation, carbamate formation, ureaformation, SRN1 substitution, aryl amination and reductive amination.

The group R3 may be modified at an appropriate stage to have the desireddefinition as set forth in the claims be standard nitrogen protectinggroup chemistry as known in the art or as described herein.

Route AIX:

In step a) standard methods for the introduction of the primary amineare employed, such as using: an NH3 equivalent [e.g. NH3/EtOH, NH4Cl,NH4OH], a hydride reagent [e.g. NaBH(OAc)₃, NaBH(CN)3 or a combinationof Ti(OiPr)4 with hydride agents such as NaBH4]

i) either simultaneous treatment with or stepwise treatment via imineformation with BnNH2, a hydride reagent (see above), or ii) cat.hydrogenation

i) either simultaneous treatment with or stepwise treatment via imineformation with PMBNH2, hydride reagent (see above), or ii) CAN or DDQ(oxidative debenzylation) or TFA

i) RONH2 [oxime formation] ii) Na or BH3 or cat. hydrogenation (e.g.Ra—Ni, Pd—C, Pt—C) [reduction of oxime] whereby R is for example benzyl,p-methoxybenzyl, or allyl.

i) a hydride reagent [reduction to alcohol] ii) Mitsunobu conditionusing PPh3, DEAD, N3 anion or mesylation with MsCl and base then N3anion or bromination with conditions such as NBS/PPh3, PBr3/PPh3,CBr4/PPh3 then N3 anion or PBr3/PPh3 then N3 anion iii) PR3 or cat.Hydrogenation [reduction of azide] whereby R is for example ethyl orphenyl

In steps b) and c), group R1 or the benzyl ring, respectively, areintroduced by usual functional group manipulation in the amine, such asalkylation, carbamate formation, urea formation, SRN1 substitution, arylamination and reductive amination for step b) and preferably alkylationand reductive amination for step c).

The group R3 may be modified at an appropriate stage to have the desireddefinition as set forth in the claims be standard nitrogen protectinggroup chemistry as known in the art or as described herein.

Route AX:

wherein LG is a leaving group such as a mesylate, tosylate, triflate orbromide.

In step a) standard methods to reduce the carbonyl group are employed,such as the use of a hydride agent, e.g. NaBH4 or K-Selectride.

In step b) standard methods for the conversion of the alcohol to aleaving group (LG; e.g. a mesylate, tosylate, or bromide) are employed.The methods include the use of MsCl/base or TsCl/base or SOCl2 orNBS/PPh3 or CBr4/PPh3 or Tf2O using conditions well known in the art.

In step c) the amine unit is introduced using standard substitutionchemistry, e.g. by employing the secondary amine and a strong base suchas NaH, KOt-Bu, LHMDS.

The group R3 may be modified at an appropriate stage to have the desireddefinition as set forth in the claims be standard nitrogen protectinggroup chemistry as known in the art or as described herein.

Route XI:

A two step one pot new synthesis is also possible. An intermediate maybe prepared via a double mannich reaction by alkylaldehyde,1,3-dicarboxylic acetone and ammonium. R2 and R4 are equivalent is thiscase in that R2 and R4 come from the same alkylaldehyde startingmaterial.

In step a) the nitrogen is protected by appropriate protection group(e.g. Boc group).

The group R3 may be modified at an appropriate stage to have the desireddefinition as set forth in the claims be standard nitrogen protectinggroup chemistry as known in the art or as described herein.

In step b) standard methods for reductive amination are employed, suchas ArCH2NH2, hydride reagent [ex. NaBH(OAc)3, NaBH(CN)3, NaBH4, LiBH4,BH3, picoline borane, borane-pyridine complex]; or Ti(OiPr)4; thenhydride reagent such as NaBH(OAc)3, NaBH(CN)3, NaBH4, LiBH4, borane,picoline borane, borane-pyridine complex, LiAlH4,9-BBN, Alpine borane,LiB(s-Bu)3H, LiB(Sia)₃H; or imine formation catalyzed or uncatalyzed byacid followed by reduction by hydride agents.

2. General Procedure B: Using Ritter-Type Chemistry

Details for preparing benzyl-substituted piperidine B1 can be found inbioorganic & Medical Chemistry Letters, Vol. 6, No. 24, pp. 3029-3034,1996. The methods described therein could be applied analogouslyobtaining substituted piperidines.

This piperidine could also be further reacted to form a compound offormula (I) by alkylation methods and nitrogen protecting groupmanipulations as described above in the procedure A.

2. General Procedure C: Using Dieckmann Chemistry

Compounds of formula (I) can be prepared be following the syntheticroute outlined in Journal of Medicinal Chemistry, 2001, Vol. 44, No. 6,pp. 972-987 either directly or analogously.

2. General Procedure D: Using Diels-Alder Chemistry

Compounds of formula (I) can be prepared be following the syntheticroutes outlined in Tetrahedron Letters, 1999, Vol. 55, No. 6, pp.7601-7612 or Org. Lett., Vol. 9, No. 21, 2002 pp. 3667-3670 eitherdirectly or analogously and converting the obtained piperidinone bymethods outlined in e.g. routes AVIII, AIX or AX above.

Racemates and diastereomer mixtures obtained can be separated into thepure isomers or racemates in a known manner on the basis of thephysicochemical differences of the components, for example by fractionalcrystallization or by chiral chromatography or HPLC separation utilizingchiral stationery phases. Racemates obtained may furthermore be resolvedinto the optical antipodes by known methods, for example byrecrystallization from an optically active solvent, chromatography onchiral adsorbents, with the aid of suitable microorganisms, by cleavagewith specific immobilized enzymes, via the formation of inclusioncompounds, for example using chiral crown ethers, only one enantiomerbeing complexed, or by conversion into diastereomeric salts, for exampleby reaction of a basic final substance racemate with an optically activeacid, such as a carboxylic acid, for example tartaric or malic acid, orsulfonic acid, for example camphorsulfonic acid, and separation of thediastereomer mixture obtained in this manner, for example on the basisof its differing solubilities, into the diastereomers from which thedesired enantiomer can be liberated by the action of suitable agents.The more active enantiomer is advantageously isolated.

In starting compounds and intermediates which are converted to thecompounds of the invention in a manner described herein, functionalgroups present, such as amino, thiol, carboxyl and hydroxy groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected amino, thiol, carboxyl andhydroxy groups are those that can be converted under mild conditionsinto free amino thiol, carboxyl and hydroxy groups without the molecularframework being destroyed or other undesired side reactions takingplace.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxy group, aminogroup, etc.), the structure and stability of the molecule of which thesubstituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, e.g., in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London, N.Y. (1973); andGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wileyand Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably, such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents, respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures, preferably ator near the boiling point of the solvents used, and at atmospheric orsuper-atmospheric pressure. The preferred solvents, catalysts andreaction conditions are set forth in the appended illustrative Examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known per se.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention and apharmaceutically acceptable carrier. The pharmaceutical composition canbe formulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,etc. In addition, the pharmaceutical compositions of the presentinvention can be made up in a solid form including capsules, tablets,pills, granules, powders or suppositories, or in a liquid form includingsolutions, suspensions or emulsions. The pharmaceutical compositions canbe subjected to conventional pharmaceutical operations such assterilization and/or can contain conventional inert diluents,lubricating agents, or buffering agents, as well as adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifers and buffers etc.

Preferably, the pharmaceutical compositions are tablets and gelatincapsules comprising the active ingredient together with

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;

b) lubricants, e.g., silica, talcum, stearic acid, its magnesium orcalcium salt and/or polyethyleneglycol; for tablets also

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired

d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt,or effervescent mixtures; and/or

e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art. Suitable compositions for oral administration includean effective amount of a compound of the invention in the form oftablets, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use are prepared according to any methodknown in the art for the manufacture of pharmaceutical compositions andsuch compositions can contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with nontoxic pharmaceutically acceptable excipients which aresuitable for the manufacture of tablets. These excipients are, forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example, starch, gelatin or acacia; and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets are uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example, peanut oil, liquid paraffin orolive oil.

Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, preferably about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with carrier. Advantageouscarriers include absorbable pharmacologically acceptable solvents toassist passage through the skin of the host. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound of the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The invention likewise relates to a combination of a compound of formula(I), (I A) or (I B), respectively, or a pharmaceutically acceptable saltthereof with a further active principle.

The combination may be made for example with the following activeprinciples, selected from the group consisting of a:

(i) HMG-Co-A reductase inhibitor or a pharmaceutically acceptable saltthereof,

(ii) angiotensin II receptor antagonist or a pharmaceutically acceptablesalt thereof,

(iii) angiotensin converting enzyme (ACE) Inhibitor or apharmaceutically acceptable salt thereof,

(iv) calcium channel blocker or a pharmaceutically acceptable saltthereof,

(v) aldosterone synthase inhibitor or a pharmaceutically acceptable saltthereof,

(vi) aldosterone antagonist or a pharmaceutically acceptable saltthereof,

(vii) dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP)inhibitor or a pharmaceutically acceptable salt thereof,

(viii) endothelin antagonist or a pharmaceutically acceptable saltthereof,

(ix) renin inhibitor or a pharmaceutically acceptable salt thereof,

(x) diuretic or a pharmaceutically acceptable salt thereof, and

(xi) an ApoA-1 mimic.

An angiotensin 11 receptor antagonist or a pharmaceutically acceptablesalt thereof is understood to be an active ingredients which bind to theAT1-receptor subtype of angiotensin II receptor but do not result inactivation of the receptor. As a consequence of the inhibition of theAT1 receptor, these antagonists can, for example, be employed asantihypertensives or for treating congestive heart failure.

The class of AT1 receptor antagonists comprises compounds havingdiffering structural features, essentially preferred are thenon-peptidic ones. For example, mention may be made of the compoundswhich are selected from the group consisting of valsartan, losartan,candesartan, eprosartan, irbesartan, saprisartan, tasosartan,telmisartan, the compound with the designation E-1477 of the followingformula

the compound with the designation SC-52458 of the following formula

and the compound with the designation ZD-8731 of the following formula

or, in each case, a pharmaceutically acceptable salt thereof.

Preferred AT1-receptor antagonist are those agents which have beenmarketed, most preferred is valsartan or a pharmaceutically acceptablesalt thereof.

HMG-Co-A reductase inhibitors (also called-hydroxy-methylglutaryl-co-enzyme-A reductase inhibitors) are understoodto be those active agents that may be used to lower the lipid levelsincluding cholesterol in blood.

The class of HMG-Co-A reductase inhibitors comprises compounds havingdiffering structural features. For example, mention may be made of thecompounds that are selected from the group consisting of atorvastatin,cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin,fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin,rivastatin, simvastatin, and velostatin, or, in each case, apharmaceutically acceptable salt thereof.

Preferred HMG-Co-A reductase inhibitors are those agents which have beenmarketed, most preferred is fluvastatin and pitavastatin or, in eachcase, a pharmaceutically acceptable salt thereof.

The interruption of the enzymatic degradation of angiotensin I toangiotensin II with so-called ACE-inhibitors (also called angiotensinconverting enzyme inhibitors) is a successful variant for the regulationof blood pressure and thus also makes available a therapeutic method forthe treatment of congestive heart failure.

The class of ACE inhibitors comprises compounds having differingstructural features. For example, mention may be made of the compoundswhich are selected from the group consisting alacepril, benazepril,benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril,enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril,quinapril, ramipril, spirapril, temocapril, and trandolapril, or, ineach case, a pharmaceutically acceptable salt thereof.

Preferred ACE inhibitors are those agents that have been marketed, mostpreferred are benazepril and enalapril.

The class of CCBs essentially comprises dihydropyridines (DHPs) andnon-DHPs such as diltiazem-type and verapamil-type CCBs.

A CCB useful in said combination is preferably a DHP representativeselected from the group consisting of amlodipine, felodipine, ryosidine,isradipine, lacidipine, nicardipine, nifedipine, niguldipine,niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, andis preferably a non-DHP representative selected from the groupconsisting of flunarizine, prenylamine, diltiazem, fendiline,gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in eachcase, a pharmaceutically acceptable salt thereof. All these CCBs aretherapeutically used, e.g. as anti-hypertensive, anti-angina pectoris oranti-arrhythmic drugs. Preferred CCBs comprise amlodipine, diltiazem,isradipine, nicardipine, nifedipine, nimodipine, nisoldipine,nitrendipine, and verapamil, or, e.g. dependent on the specific CCB, apharmaceutically acceptable salt thereof. Especially preferred as DHP isamlodipine or a pharmaceutically acceptable salt, especially thebesylate, thereof. An especially preferred representative of non-DHPs isverapamil or a pharmaceutically acceptable salt, especially thehydrochloride, thereof.

Aldosterone synthase inhibitor is an enzyme that converts corticosteroneto aldosterone to by hydroxylating cortocosterone to form18-OH-corticosterone and 18-OH-corticosterone to aldosterone. The classof aldosterone synthase inhibitors is known to be applied for thetreatment of hypertension and primary aldosteronism comprises bothsteroidal and non-steroidal aldosterone synthase inhibitors, the laterbeing most preferred.

Preference is given to commercially available aldosterone synthaseinhibitors or those aldosterone synthase inhibitors that have beenapproved by the health authorities.

The class of aldosterone synthase inhibitors comprises compounds havingdiffering structural features. For example, mention may be made of thecompounds which are selected from the group consisting of thenon-steroidal aromatase inhibitors anastrozole, fadrozole (including the(+)-enantiomer thereof), as well as the steroidal aromatase inhibitorexemestane, or, in each case where applicable, a pharmaceuticallyacceptable salt thereof.

The most preferred non-steroidal aldosterone synthase inhibitor is the(+)-enantiomer of the hydrochloride of fadrozole (U.S. Pat. Nos.4,617,307 and 4,889,861) of formula

A preferred steroidal aldosterone antagonist is eplerenone of theformula

spironolactone.

A preferred dual angiotensin converting enzyme/neutral endopetidase(ACE/NEP) inhibitor is, for example, omapatrilate (cf. EP 629627),fasidotril or fasidotrilate, or, if appropriable, a pharmaceuticallyacceptable salt thereof.

A preferred endothelin antagonist is, for example, bosentan (cf. EP526708 A), furthermore, tezosentan (cf. WO 96/19459), or in each case, apharmaceutically acceptable salt thereof.

A renin inhibitor is, for example, a non-peptidic renin inhibitor suchas the compound of formula

chemically defined as2(S),4(S),5(S),7(S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)-4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxy-propoxy)phenyl]-octanamide.This representative is specifically disclosed in EP 678503A. Especiallypreferred is the hemi-fumarate salt thereof.

A diuretic is, for example, a thiazide derivative selected from thegroup consisting of chlorothiazide, hydrochlorothiazide,methylclothiazide, and chlorothalidon. The most preferred ishydrochlorothiazide.

An ApoA-I mimic is, for example, D4F peptide, especially of formulaD-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F

Preferably, the jointly therapeutically effective amounts of the activeagents according to the combination of the present invention can beadministered simultaneously or sequentially in any order, separately orin a fixed combination.

The structure of the active agents identified by generic or tradenamesmay be taken from the actual edition of the standard compendium “TheMerck Index” or from databases, e.g. IMS LifeCycle (e.g. IMS WorldPublications). The corresponding content thereof is hereby incorporatedby reference. Any person skilled in the art is fully enabled to identifythe active agents and, based on these references, likewise enabled tomanufacture and test the pharmaceutical indications and properties instandard test models, both in vitro and in vivo.

Furthermore, the combinations as described above can be administered toa subject via simultaneous, separate or sequential administration (use).Simultaneous administration (use) can take place in the form of onefixed combination with two or more active ingredients, or bysimultaneously administering two or more compounds that are formulatedindependently. Sequential administration(use) preferably meansadministration of one (or more) compounds or active ingredients of acombination at one time point, other compounds or active ingredients ata different time point, that is, in a chronically staggered manner,preferably such that the combination shows more efficiency than thesingle compounds administered independently (especially showingsynergism). Separate administration (use) preferably meansadministration of the compounds or active ingredients of the combinationindependently of each other at different time points, preferably meaningthat two compounds are administered such that no overlap of measurableblood levels of both compounds are present in an overlapping manner (atthe same time).

Also combinations of two or more of sequential, separate andsimultaneous administrations are possible, preferably such that thecombination compound-drugs show a joint therapeutic effect that exceedsthe effect found when the combination compound-drugs are usedindependently at time intervals so large that no mutual effect on theirtherapeutic efficiency can be found, a synergistic effect beingespecially preferred.

Additionally, the present invention provides:

-   -   a pharmaceutical composition or combination of the present        invention for use as a medicament;    -   the use of a pharmaceutical composition or combination of the        present invention for the delay of progression and/or treatment        of a disorder or disease mediated by CETP or responsive to the        inhibition of CETP.    -   the use of a pharmaceutical composition or combination of the        present invention for the delay of progression and/or treatment        of a disorder or disease selected from hyperlipidemia,        arteriosclerosis, atherosclerosis, peripheral vascular disease,        dyslipidemia, hyperbetalipoproteinemia,        hypoalphalipoproteinemia, hypercholesterolemia,        hypertriglyceridemia, familial hypercholesterolemia,        cardiovascular disorder, coronary heart disease, coronary artery        disease, coronary vascular disease, angina, ischemia, heart        ischemia, thrombosis, cardiac infarction such as myocardial        infarction, stroke, peripheral vascular disease, reperfusion        injury, angioplasty restenosis, hypertension, congestive heart        failure, diabetes such as type II diabetes mellitus, diabetic        vascular complications, obesity or endotoxemia etc.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredients for asubject of about 50-70 kg, preferably about 5-500 mg of activeingredients. The therapeutically effective dosage of a compound, thepharmaceutical composition, or the combinations thereof, is dependent onthe species of the subject, the body weight, age and individualcondition, the disorder or disease or the severity thereof beingtreated. A physician, clinician or veterinarian of ordinary skill canreadily determine the effective amount of each of the active ingredientsnecessary to prevent, treat or inhibit the progress of the disorder ordisease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., preferably aqueous solutions, and in vivo either enterally,parenterally, advantageously intravenously, e.g., as a suspension or inaqueous solution. The dosage in vitro may range between about 10-3 molarand 10-9 molar concentrations. A therapeutically effective amount invivo may range depending on the route of administration, between about0.1-500 mg/kg, preferably between about 1-100 mg/kg.

The CETP inhibitory effect of the compounds of the present invention canbe determined by using the test models or assays known in the art. Forexample, EP1115695B1 describes both the in vitro and in vivo CETPactivity assays, the contents of which are hereby incorporated byreference. In particular, the following assays are used.

(1) CETP In Vitro Assay:

CETP Activity Kit (#RB-RPAK) was purchased from Roar Biochemical, Inc.(New York, N.Y., USA). To each well of a 96-well NBS half-area plate(costar #3686), 1.2 ng/well of the donor solution, 1 μL of the acceptorsolution and 5 μL compound solution diluted in 100% DMSO were added in a38 μL of buffer containing 10 mM Tris, 150 mM NaCl and 2 mM EDTA, pH7.4. Then, the plate was sealed with Themowell™ Sealers (costar #6524)and followed by a mixing on a plate shaker by MICROPLATE MIXER MPX-96(IWAKI) at power 3 for 10 sec at room temperature. After 10-minincubation at 37° C., the reaction was started by adding 5 μL of rhCETPsolution (Cardiovascular Target, New York, N.Y., USA) and mixed on theplate shaker for 10 sec, then the fluorescence intensity at 0 min wasmeasured by a ARVO SX (Perkin Elmerr, USA) at excitation wavelength of465 nm and emission wavelength of 535 nm. After 120 min-incubation at37° C., fluorescence intensity was measured again. The inhibition ofrhCETP activity by a compound was calculated by the followingcalculation. Inhibition %={1−(F120−F0)/(f120−f0)}×100 F: measuredfluorescence intensity with compound at 0 or 120 min. f: measuredfluorescence intensity of without compound at 0 or 120 min.

The IC50 values are determined from the dose-effect curve by Originsoftware. IC50 values, especially from about 0.1 nM to about 50 μM, aredetermined for the compounds of the present invention or apharmaceutically acceptable salt thereof.

(2) Effects on Plasma HDL Levels in Hamster:

Effects of compounds on HDL-cholesterol level in hamsters areinvestigated by the method reported previously with some modifications(Eur, J. Pharmacol, 466 (2003) 147-154). In brief, male Syrian hamsters(10-11 week-old age, SLC, Shizuoka, Japan) are fed a high cholesteroldiet for two weeks. Then, the animals are dosed singly with the compoundsuspended with carboxylmethyl cellulose solution. HDL-cholesterol levelsare measured by using commercially available kit (Vako Pure Chemical,Japan) after the precipitation of apolipoprotein B (apoB)-containinglipoproteins with 13% polyethylene glycol 6000.

(3) Preparation of Human pro-Apolipoprotein AI (pro-apoAI)

The cDNA of human pro-apoAI (NCBI accession number: NM_(—)000039) iscloned from human liver Quick-Clone™ cDNA (Clontech, CA) and inserted toa pET28a vector (Novagen, Germany) for bacterial expression. Expressedprotein as a fusion protein with 6×His-tag at N-terminus in BL-21 Gold(DE3) (Strategene, CA) is purified using HiTrap Chelating (GEHealthcare, CT).

(4) Preparation of Donor Microemulsion

Pro-apoAI containing microemulsion as a donor particle is preparedfollowing previous reports (J. Biol. Chem., 280:14918-22). Glyceryltrioleate (62.5 ng, Sigma, Mo.), 3-sn-phosphatidylcholine (583 ng, WakoPure Chemical Industries, Japan), and cholesteryl BODIPY® FL C12 (250ng, Invitrogen, CA) are dissolved in 1 mL of chloroform. The solution isevaporated, then residual solvent is removed in vacuum for more than 1hr. The dried lipid mixture is dissolved in 500 μL of the assay buffer(50 mM Tris-HCl (pH7.4) containing 150 mM NaCl and 2 mM EDTA) andsonicated at 50° C. with a microtip (MICROSON™ ULTRASONIC CELLDISRUPTOR, Misonix, Farmingdale, N.Y.) at output power 006 for 2 min.After sonication, the solution is cooled to 40° C., added to 100 μg ofhuman pro-apoAI, and sonicated at output power 004 for 5 min at 40° C.The solution, BODIPY-CE microemulsion as a donor molecule is stored at4° C. after filtration through a 0.45 μm PVDF filter.

(5) In Vitro CETP Activity Assay in Human Plasma

Human EDTA plasma samples from healthy men are purchased from New DrugDevelopment Research Center, Inc. Donor solution is prepared by adilution of donor microemulsion with assay buffer. Human plasma (50 μL),assay buffer (35 μL) and test compound dissolved in dimethylsulfoxide (1μL) are added to each well of 96 well half area black flat bottom plate.The reaction is started by the addition of donor solution (14 μL) intoeach well. Fluorescence intensities are measured every 30 min at 37° C.with excitation wave length of 485 nm and emission wavelength of 535 nm.The CETP activity (FI/min) is defined as the changes of fluorescenceintensity from 30 to 90 min. The IC50 value is obtained by the logisticequation (Y=Bottom+(Top−Bottom)/(1+(x/IC50)^Hill slope) using Originsoftware, version 7.5 SR3. The compounds of formula I exhibit inhibitoryactivity with an IC50 value in the range from approximately from 0.001to 100 μM, especially from 0.01 to 10 μM.

The compounds of the present invention or a pharmaceutically acceptablesalt thereof have superior CETP inhibitory activity in mammals (e.g.,human, monkey, bovine, horse, dog, cat, rabbit, rat, mouse and thelike), and can be used as CETP activity inhibitors. In addition,utilizing the superior CETP inhibitory activity of a compound of thepresent invention or a pharmaceutically acceptable salt thereof, thecompounds of the present invention are useful as pharmaceutical agentseffective for the prophylaxis or treatment of or delay progression toovert to diseases in which CETP is involved (e.g., hyperlipidemia,arteriosclerosis, atherosclerosis, peripheral vascular disease,dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, cardiovascular disorder, coronary heart disease,coronary artery disease, coronary vascular disease, angina, ischemia,heart ischemia, thrombosis, cardiac infarction such as myocardialinfarction, stroke, peripheral vascular disease, reperfusion injury,angioplasty restenosis, hypertension, congestive heart failure, diabetessuch as type II diabetes mellitus, diabetic vascular complications,obesity or endotoxemia etc.), particularly as prophylactic ortherapeutic agents for hyperlipidemia or arteriosclerotic diseases.

TABLE 1 Inhibitory Activity of Compounds Compound IC50 (nM) Example 1-2142 Example 1-5 135 Example 1-8 69 Example 1-11 63 Example 1-17 86Example 1-19 98 Example 1-20 91 Example 1-22 99 Example 1-27 152 Example4 68AbbreviationsAc: Acetylaq: aqueousAr: aromaticBBN: borabicyclo[3.3.1]nonanedba:dibenzylidenacetoneBn: benzylBoc: tert-butoxycarbonylCAN: ceric ammonium nitrateDDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinoneDEAD: diethyl azodicarboxylateDIPEA: N,N-diisopropylethylamineDMAP: N,N-dimethylaminopyridineDME: dimethoxyethaneDMME: dimethoxymethaneDMMIM: 1-butyl-3-methylimidazoliumDMF: N,N-dimethylformamideDMSO: dimethyl sulfoxidedppf: 1,1-bis(diphenylphosphino)ferroceneEDTA: ethylenediaminetetraacetic acidESI: electrospray ionizationEt: ethylEtOAc: ethyl acetateh: hoursHCl: hydrogen chlorideHPLC: high pressure liquid chromatographyIPA: 2-propanoliPr: isopropylIR: infraredKHMDS: potassium hexamethyldisilamideLC: liquid chromatographyLDA: lithium diisopropylamideLHMDS: lithium hexamethyldisilamideMe: methylmin: minutesMS: mass spectrometryMs: mesylNBS: N-bromosuccinimideNMR: nuclear magnetic resonancePh: phenylPMB: p-methoxybenzylRP: reversed phaseRT: room temperatures-Bu: sec-butylSia: siamylSFC: supercritical fluid chromatographyTBAI: tetrabutylammonium iodideTf: triflateTFA: trifluoroacetic acidTHF: tetrahydrofuranTLC: thin layer chromatographyTs: tosyltBu: tert-butyltol: tolyl

EXAMPLES

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art. The compoundsin the following examples have been found to have IC50 values in therange of about 0.1 nM to about 10,000 nM for CETP.

The conditions for measuring the retention times are as follows:

Condition A (HPLC)

Column: ACQUITY UPLCTM BEH C18 1.7 um, 50×2.1 mm.

Flow rate: 0.5 ml 1 min

Mobile phase: A) TFA/water (0.1/100, v/v), B) TFA/acetonitrile (0.1/100,v/v)

Gradient: 5% B in 0.5 min, then linear gradient from 5% B to 100% B in1.5 min then 100% B in 1 min

Detection: UV at 215 nm

Condition B (HPLC)

Column: ACQUITY UPLCTM BEH C18 1.7 um, 50×2.1 mm.

Flow rate: 0.5 ml/min

Mobile phase: A) TFA/water (0.1/100, v/v), B) TFA/acetonitrile (0.1/100,v/v)

Gradient: 5% B in 0.5 min, then linear gradient from 5% B to 100% B in5.0 min then 100% B in 1.5 min

Detection: UV at 215 nm

Condition C (HPLC)

Column: CombiScreen ODS-AM, 50×4.6 mm.

Flow rate: 2.0 ml/min

Mobile phase: A) TFA/water (0.1/100, v/v), B) TFA/acetonitrile (0.1/100,v/v)

Gradient: linear gradient from 5% B to 100% B in 5 min then 100% B in 2min

Detection: UV at 215 nm

Examples Example 1 Synthesis of(4-{cis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carbonyl}-cyclohexyl)-aceticacid

To a solution of(4-{cis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carbonyl}-cyclohexyl)-aceticacid ethyl ester (41 mg, 0.0511 mmol) in THF (1.79 ml) and H2O (0.51ml), aqueous 1M LiOH (255 uL) is added at room temperature. The mixtureis stirred at room temperature for 18 hours. To the mixture, aqueous 1MHCl (255 uL) and H2O is added. The solution is extracted withdichloromethane, and the organic layer is concentrated under reducedpressure. The obtained residue is purified by reverse-phase HPLC to give(4-{cis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-6-ethyl-piperidine-1-carbonyl}-cyclohexyl)-aceticacid (24.1 mg, 60.8%); ESI-MS m/z: 776 [M+1]+, Retention time 4.56 min(condition B).

The following compounds are prepared following the procedure of Example1

ESI-MS m/z Retention No Product [M + 1]+ time (min) Starting Material 1

714 2.17 (condition A)

2

709 2.16 (condition A)

3

695 2.10 (condition A)

4

671 2.15 (condition A)

5

685 2.17 (condition A)

6

685 2.19 (condition A)

7

711 4.38 (condition B)

8

711 4.56 (condition B)

Use 1M NaOH instead 9

657 2.11 (condition A)

10

716 2.23 (condition A)

11

713 2.23 (condition A)

12

698 1.90 (condition A)

Use 1M NaOH instead of 1M LiOH 13

716 4.14 (condition B)

14

716 2.19 (condition A)

Use 1M NaOH instead of 1M LiOH 15

690 1.94 (condition A)

Use 1M NaOH instead of 1M LiOH 16

729 2.21 (condition A)

Use 1M NaOH instead of 1M LiOH 17

683 2.18 (condition A)

18

699 2.18 (condition A)

19

683 2.17 (condition A)

Use 1M NaOH instead of 1M LiOH 20

643 4.72 (condition B)

21

725 2.37 (condition A)

22

661 4.42 (condition B)

23

711 2.30 (condition A)

24

691 2.34 (condition A)

25

697 2.23 (condition A)

26

778 2.33 (condition A)

27

725 2.35 (condition A)

28

709 2.54 (condition A)

No. 1H NMR 2 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.79-0.95 (m, 6 H)0.99-1.17 (m, 2 H) 1.36-1.49 (m, 1 H) 1.64-1.98 (m, 12 H) 2.08-2.31 (m,4 H) 2.41-2.52 (m, 1 H) 3.89-3.96 (m, 1 H) 4.01 (s, 3 H) 4.50-4.62 (m, 1H) 4.64-4.76 (m, 1 H) 4.89 (d, J=3.28 Hz, 2 H) 7.60 (s, 1 H) 7.70 (s, 2H) 7.77 (s, 2 H) 8.47 (s, 2 H) 3 1H NMR (400 MHz, CHLOROFORM-d) δ ppm0.80-0.94 (m, 6 H) 1.00-1.15 (m, 2 H) 1.37-1.49 (m, 1 H) 1.57-2.00 (m,13 H) 2.07-2.35 (m, 4 H) 2.41-2.53 (m, 1 H) 3.89-4.00 (m, 1 H) 4.52-4.63(m, 1 H) 4.68-4.79 (m, 1 H) 4.90 (s, 2 H) 7.70 (s, 2 H) 7.77 (s, 1 H)7.96 (s, 2 H) 8.51 (s, 2 H) 4 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85(t, J=7.33 Hz, 6 H) 1.30-1.51 (m, 6 H) 1.64-1.78 (m, 2 H) 2.03-2.18 (m,2 H) 2.22-2.32 (m, 2 H) 2.47-2.54 (m, 2 H) 3.94 (s, 3 H) 4.25-4.35 (m, 2H) 4.58-4.69 (m, 1 H) 4.88 (br. s., 2 H) 7.55 (s, 1 H) 7.66 (s, 1 H)7.70 (s, 2 H) 7.76 (s, 1 H) 8.43 (s, 2 H) 5 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.86 (t, J=7.33 Hz, 6 H) 1.40-1.51 (m, 4 H)1.68-1.90 (m, 6 H) 2.13-2.24 (m, 2 H) 2.42-2.48 (m, 2 H) 3.94 (s, 3 H)4.13-4.23 (m, 2 H) 4.24-4.35 (m, 2 H) 4.63-4.75 (m, 1 H) 4.87 (s, 2 H)7.56 (s, 1 H) 7.67 (s, 1 H) 7.69 (s, 2 H) 7.75 (s, 1 H) 8.55 (s, 2 H) 61H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.86 (t, J=7.33 Hz, 6 H) 1.30 (s, 6H) 1.39-1.54 (m, 4 H) 1.67-1.80 (m, 2 H) 2.12-2.21 (m, 2 H) 3.95 (s, 3H) 4.17-4.36 (m, 4 H) 4.54-4.66 (m, 1 H) 4.86 (s, 2 H) 7.56 (s, 1 H)7.67 (s, 1 H) 7.69 (s, 2 H) 7.75 (s, 1 H) 8.46 (s, 2 H) 7 1H NMR (400MHz, CHLOROFORM-d) δ ppm 0.86 (t, J=7.45 Hz, 6 H) 1.41-1.58 (m, 4 H)1.60-1.70 (m, 2 H) 1.78-1.88 (m, 6 H) 1.89-1.97 (m, 2 H) 2.11-2.21 (m, 2H) 2.40-2.50 (m, 1 H) 3.95 (s, 3 H) 4.13-4.22 (m, 2 H) 4.76-4.84 (m, 1H) 4.86 (s, 2 H) 4.94 (m, 1 H) 7.53 (s, 1 H) 7.67 (s, 1 H) 7.71 (s, 2 H)7.75 (s, 1 H) 8.43 (s, 2 H) 8 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85(t, J=7.30 Hz, 6 H) 1.36-1.70 (m, 7 H) 1.75-1.85 (m, 3 H) 2.03-2.20 (m,6 H) 2.31-2.41 (m, 1 H) 3.95 (s, 3 H) 4.11-4.22 (m, 2 H) 4.61-4.71 (m, 1H) 4.76-4.88 (m, 1 H) 4.86 (s, 2 H) 7.53 (s, 1 H) 7.66 (s, 1 H) 7.70 (s,2 H) 7.75 (s, 1 H) 8.43 (s, 2 H) 9 1H NMR (400 MHz, CHLOROFORM-d) δ ppm0.86 (t, J=7.33 Hz, 6 H) 1.40-1.54 (m, 4 H) 1.68-1.81 (m, 2 H) 2.13-2.21(m, 2 H) 2.75 (t, J=6.06 Hz, 2 H) 3.97 (s, 3 H) 4.21-4.31 (m, 2 H)4.42-4.48 (m, 2 H) 4.59-4.69 (m, 1 H) 4.87 (s, 2 H) 7.57 (s, 1 H) 7.69(s, 2 H) 7.70 (s, 1 H) 7.76 (s, 1 H) 8.47 (s, 2 H) 10 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.84 (t, J=7.45 Hz, 6 H) 1.35-1.53 (m, 6 H)1.55-1.67 (m, 2 H) 1.74-1.83 (m, 2 H) 2.03-2.18 (m, 6 H) 2.30-2.40 (m, 1H) 2.99-3.05 (m, 4 H) 3.83-3.87 (m, 4 H) 4.10-4.19 (m, 2 H) 4.62-4.76(m, 2 H) 4.79 (s, 2 H) 7.69 (s, 2 H) 7.73 (s, 1 H) 8.09 (s, 2 H) 12 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 0.85 (t, J=7.33 Hz, 6 H) 1.41-1.61 (m,4 H) 1.75-1.83 (m, 2 H) 2.12-2.21 (m, 2 H) 3.67-3.85 (m, 4 H) 3.94 (s, 3H) 4.07-4.17 (m, 2 H) 4.52-4.65 (m, 2 H) 4.72-4.83 (m, 1 H) 4.86 (s, 2H) 5.17-5.27 (m, 1 H) 7.54 (s, 1 H) 7.66 (s, 1 H) 7.70 (s, 2 H) 7.75 (s,1 H) 8.44 (s, 2 H) 13 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.84 (t,J=7.30 Hz, 6 H) 1.38-1.48 (m, 6 H) 1.74-1.84 (m, 3 H) 2.05-2.24 (m, 6 H)2.32-2.41 (m, 1 H) 3.19-3.29 (m, 2 H) 3.40-3.50 (m, 2 H) 4.10-4.18 (m, 2H) 4.59-4.72 (m, 3 H) 4.76 (s, 2 H) 7.68-7.75 (m, 3 H) 7.86 (s, 2 H) 141H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85 (t, J=7.33 Hz, 6 H) 1.35-1.48(m, 3 H) 1.49-1.68 (m, 5 H) 1.73-1.85 (m, 2 H) 2.03-2.18 (m, 6 H)2.30-2.43 (m, 1 H) 4.00 dd, 2 H) 4.10-4.19 (m, 2 H) 4.53 (dd, 2 H)4.62-4.78 (m, 2 H) 4.83 (s, 2 H) 7.68 (s, 2 H) 7.75 (s, 1 H) 8.51 (s, 2H) 15 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.84 (t, J=7.45 Hz, 6 H)1.36-1.69 (m, 7 H) 1.73-1.82 (m, 2 H) 2.02-2.18 (m, 7 H) 2.30-2.40 (m, 1H) 3.23 (dd, 2 H) 3.84 (dd, 2 H) 4.10-4.20 (m, 2 H) 4.61-4.74 (m, 2 H)4.76 (s, 2 H) 7.69 (s, 2 H) 7.72 (s, 1 H) 7.94 (s, 2 H) 16 1H NMR (400MHz, CHLOROFORM-d) δ ppm 0.84 (t, J=7.45 Hz, 6 H) 1.38-1.68 (m, 8 H)1.72-1.87 (m, 2 H) 2.01-2.18 (m, 6 H) 2.28-2.41 (m, 1 H) 2.89 (s, 3 H)3.50 (dd, 2 H) 3.74 (dd, 2 H) 4.08-4.18 (m, 2 H) 4.62-4.78 (m, 2 H) 4.82(s, 2 H) 7.69 (s, 2 H) 7.73 (s, 1 H) 8.52 (s, 2 H) 17 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.86 (t, J=7.33 Hz, 6 H) 1.40-1.61 (m, 4 H)1.74-1.84 (m, 2 H) 2.11-2.22 (m, 2 H) 2.33-2.46 (m, 2 H) 2.67-2.78 (m, 2H) 3.09-3.19 (m, 1 H) 3.96 (s, 3 H) 4.09-4.23 (m, 2 H) 4.74-4.84 (m, 1H) 4.87 (s, 2 H) 5.16-5.24 (m, 1 H) 7.54 (s, 1 H) 7.67 (s, 1 H) 7.71 (s,2 H) 7.75 (s, 1 H) 8.44 (s, 2 H) 18 1H NMR (400 MHz, CHLOROFORM-d) δ ppm0.74 (t, J=7.05 Hz, 3 H) 1.20-1.54 (m, 9 H) 1.62-1.76 (m, 2 H) 1.85-2.20(m, 7 H) 4.04-4.17 (m, 2 H) 4.42-4.58 (m, 1 H) 4.73-4.86 (m, 1 H) 4.91(br. s., 2 H) 7.67 (s, 2 H) 7.73 (s, 1 H) 8.63 (br. s., 2 H) 9.14 (s, 1H) 19 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (d, J=6.82 Hz, 6 H)1.37-1.49 (m, 2 H) 1.55-1.70 (m, 4 H) 2.03-2.20 (m, 6 H) 2.28-2.40 (m, 1H) 3.95 (s, 3 H) 4.31-4.44 (m, 2 H) 4.62-4.72 (m, 1 H) 4.76-4.84 (m, 1H) 4.86 (s, 2 H) 7.53 (s, 1 H) 7.66 (s, 1 H) 7.69 (s, 2 H) 7.75 (s, 1 H)8.43 (s, 2 H) 20 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.86 (t, J=7.33Hz, 6 H) 1.34-1.69 (m, 6 H) 1.72-1.85 (m, 4 H) 2.02-2.23 (m, 6 H)2.30-2.41 (m, 1 H) 3.95 (s, 3 H) 4.08-4.21 (m, 2 H) 4.62-4.70 (m, 1 H)4.71-4.82 (m, 3 H) 7.12 (d, J=1.77 Hz, 2 H) 7.22 (t, J=1.89 Hz, 1 H)7.53 (s, 1 H) 7.66 (s, 1 H) 8.43 (s, 2 H) 21 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.85 (t, J=7.30 Hz, 6 H) 1.04-1.15 (m, 2 H)1.41-1.49 (m, 4 H) 1.75-1.94 (m, 6 H) 2.03-2.21 (m, 5 H) 2.25-2.35 (m, 1H) 3.94-3.98 (m, 5 H) 4.12-4.24 (m, 2 H) 4.77-4.85 (m, 1 H) 4.88 (s, 2H) 7.54 (s, 1 H) 7.67 (s, 1 H) 7.71 (s, 2 H) 7.75 (s, 1 H) 8.44 (s, 2 H)22 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85 (t, J=7.33 Hz, 6 H)1.35-1.65 (m, 8 H) 1.73-1.85 (m, 2 H) 2.02-2.20 (m, 6 H) 2.31-2.40 (m, 1H) 3.95 (s, 3 H) 4.09-4.20 (m, 2 H) 4.61-4.72 (m, 1 H) 4.73-4.85 (m, 3H) 7.10-7.21 (m, 2 H) 7.32 (s, 1 H) 7.53 (s, 1 H) 7.66 (s, 1 H) 8.43 (s,2 H) 23 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.86 (t, J=7.33 Hz, 6 H)1.38-1.53 (m, 4 H) 1.64-1.80 (m, 9 H) 2.11-2.22 (m, 4 H) 3.95 (s, 3 H)4.22-4.36 (m, 3 H) 4.54-4.65 (m, 1 H) 4.86 (s, 2 H) 7.56 (s, 1 H) 7.66(s, 1 H) 7.68 (s, 2 H) 7.75 (s, 1 H) 8.47 (s, 2 H) 24 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.84 (t, J=7.33 Hz, 6 H) 1.35-1.53 (m, 6 H)1.74-1.83 (m, 4 H) 2.03-2.18 (m, 6 H) 2.29-2.40 (m, 1 H) 3.93-3.97 (m, 2H) 4.05-4.09 (m, 2 H) 4.10-4.20 (m, 2 H) 4.61-4.75 (m, 2 H) 4.79 (s, 2H) 7.68 (s, 2 H) 7.73 (s, 1 H) 8.11 (s, 2 H) 26 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.92 (t, J=7.30 Hz, 3 H) 1.41-1.51 (m, 6 H)1.52-1.68 (m, 4 H) 1.76-1.84 (m, 1 H) 2.05-2.21 (m, 4 H) 2.24-2.51 (m, 3H) 2.97-3.02 (m, 3 H) 3.26 (dd, J=12.59, 3.53 Hz, 1 H) 3.80-3.85 (m, 3H) 4.23-4.33 (m, 2 H) 4.62-4.74 (m, 3 H) 4.88 (d, J=16.62 Hz, 1 H)7.05-7.21 (m, 5 H) 7.62 (s, 2 H) 7.72 (s, 1 H) 8.05 (s, 2 H)

Example 2 Synthesis of(4-{cis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromopyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carbonyl}-cyclohexyl)-aceticacid

To a solution of(4-{cis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromopyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carbonyl}-cyclohexyl)-aceticacid ethyl ester (13 mg 0.0163 mmol) in dioxane (1 mL) is added aqueous5M HCl (1 mL). The mixture is stirred at 100° C. for 3 hours. Theproduct is purified by reverse-phase HPLC to give(4-{cis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromopyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carbonyl}-cyclohexyl)-aceticacid (2.3 mg, 18%); ESI-MS m/z: 769 [M+1]+, Retention time 2.61 min(condition A).

Example 3 Synthesis oftrans-4-{cis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromopyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carbonyl}-cyclohexanecarboxylicacid

To solution of trans-cyclohexane-1,4-dicarboxylic acid (135 mg, 0.784mmol) in THF (2 mL) is added thionyl chloride (572 uL, 7.84 mmol). Themixture is stirred at room temperature for 18 hours then the mixture isconcentrated under reduced pressure. The obtained residue is added to asolution of(cis-2-benzyl-6-ethylpiperidin-4-yl)-(3,5-bis(trifluoromethyl)benzyl)-(5-bromo-pyrimidin-2-yl)-aminehydrochloride (50 mg, 0.0784 mmol), triethylamine (329 uL, 2.35 mmol) inDMF (2 mL). The mixture is stirred at 150° C. for 1 hour under microwaveirradiation. To the mixture is added dichloromethane (5 mL), H2O (5 mL),and Li2CO3 (173 mg, 2.35 mmol). The mixture is stirred at roomtemperature for 2 hours and extracted with dichloromethane. The organiclayer is concentrated under reduced pressure, and the obtained residueis purified by reverse-phase HPLC to give4-{cis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromopyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carbonyl}-cyclohexanecarboxylicacid (9.0 mg, 15%); ESI-MS m/z 755 [M+1]+, Retention time 2.60 min(condition A).

The following compounds are prepared following the procedure of Example3

ESI-MS m/z Retention No Product [M + 1]+ time (min) Starting Material 1

755 2.65 (condition A)

Example 4 Synthesis ofcis-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethyl-piperidine-1-carboxylicacid 4-carbamoyl-butyl ester

To a solution ofcis-4-{(3,5-bis(trifluoromethyl)benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carboxylicacid 4-carboxy-butyl ester (50 mg, 0.0730 mmol), di-tert-butyldicarbonate (25.5 mg, 0.117 mmol), and pyridine (4.34 uL, 0.0533 mmol)in acetonitrile (1 mL) is added ammonium hydrogen carbonate (8.65 mg,0.110 mmol) at room temperature. The mixture is stirred for 15 hours atroom temperature. To the mixture, water is added and the solution isextracted with dichloromethane. The solvent is removed under reducedpressure, and the obtained residue is purified by silica gel columnchromatography to givecis-4-{(3,5-bis(trifluoromethyl)benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carboxylicacid 4-carbamoyl-butyl ester (37 mg, 74%); ESI-MS m/z: 684 [M+1]+,Retention time 2.30 min (condition A).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85 (t, J=7.33 Hz, 6H) 1.41-1.55(m, 4H) 1.69-1.85 (m, 6H) 2.10-2.21 (m, 2H) 2.29 (t, 2H) 3.95 (s, 3H)4.10-4.22 (m, 4H) 4.74-4.83 (m, 1H) 4.86 (s, 2H) 5.29 (br. s., 1H) 5.49(br. s., 1H) 7.54 (s, 1H) 7.66 (s, 1H) 7.71 (s, 2H) 7.75 (s, 1H) 8.43(s, 2H)

Example 5 Synthesis ofcis-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-imidazol-1-yl-pyrimidin-2-yl)-amino]-2,6-diethylpiperidine-1-carboxylicacid trans-4-carboxy-cyclohexyl ester

A mixture ofcis-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2,6-diethylpiperidine-1-carboxylicacid trans-4-carboxy-cyclohexyl ester (0.56 mmol, 398 mg), imidazole(1.12 mmol, 77 mg), copper iodide (0.56 mmol, 107 mg),dimethylamino-acetic acid (0.56 mmol, 58 mg) and potassium carbonate(1.68 mmol, 232 mg) in dimethyl sulfoxide (2 mL) is allowed to warm to120° C. and stirred for 67 hours. The mixture is cooled to roomtemperature and then water is added. The mixture is filtrated andextracted with CH2Cl2. The combined organic layer is concentrated underreduced pressure, and obtained residue is purified by silica gel columnchromatography (eluent: CH2Cl2/EtOH) to givecis-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-imidazol-1-yl-pyrimidin-2-yl)-amino]-2,6-diethylpiperidine-1-carboxylicacid trans-4-carboxy-cyclohexyl ester (100 mg, 26%); ESI-MS m/z: 697[M+1]+, Retention time 2.00 min (condition A).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85 (t, J=7.33 Hz, 6H) 1.36-1.51(m, 2H) 1.52-1.65 (m, 4H) 1.72-1.85 (m, 4H) 2.02-2.22 (m, 6H) 2.28-2.39(m, 1H) 4.12-4.23 (m, 2H) 4.62-4.69 (m, 1H) 4.72-4.83 (m, 1H) 4.89 (s,2H) 7.13 (s, 1H) 7.24 (s, 1H) 7.70 (s, 2H) 7.72 (s, 1H) 7.77 (s, 1H)8.39 (s, 2H)

Preparation of the starting materials can be done as follows.

Example 6 Synthesis ofcis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carboxylicacid tert-butyl ester

To a mixture ofcis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carboxylicacid tert-butyl ester (315 mg, 0.449 mmol),tris(dibenzylideneacetone)dipalladium(0) (82.3 mg, 0.0900 mmol),2-(di-tert-butylphosphino)biphenyl (53.7 mg, 0.180 mmol), and sodiumtert-butoxide (173 mg, 180 mmol) in toluene is added morpholine (78.5uL, 0.898 mmol) at room temperature under nitrogen. The mixture isstirred at 100° C. for 3 hours. After the mixture is cooled to roomtemperature, saturated aqueous NH4Cl is added, and extracted with AcOEt.The combined organic layer is washed with brine, dried over Na2SO4,filtrated, concentrated under reduced pressure, and purified by silicagel column chromatography to givecis-2-benzyl-4-[(3,5-bis(trifluoromethylbenzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carboxylicacid tert-butyl ester (265 mg, 83.4%); ESI-MS m/z 708 [M+1]+, Retentiontime 2.61 min (condition A).

The following compounds are prepared following the procedure of Example6

ESI-MS m/z Retention No Product [M + 1]+ time (min) Starting Material 1

racemate 742 2.30 (condition A)

racemate 2

646 2.43 (condition A)

Example 7 Synthesis of[trans-4-(cis-4-{(3,5-bis(trifluoromethyl)benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carbonyl)-cyclohexyl]-aceticacid ethyl ester

(trans-4-(cis-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2,6-diethylpiperidine-1-carbonyl)-cyclohexyl)-aceticacid ethyl ester (205 mg, 0.419 mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(87.2 mg, 0.419 mmol), tetrakis(triphenylphosphine)palladium(0) (32.2mg, 0.0279 mmol), and sodium carbonate (59.1 mg, 0.558 mmol) aredissolved in H2O (0.54 mL) and DME (2.7 mL) at room temperature. Themixture is stirred at 95° C. for 3 hours, and cooled to roomtemperature. To the mixture is added water and the solution is extractedwith dichloromethane. The solvent is removed under reduced pressure, andthe obtained residue is purified by silica gel column chromatography togive[trans-4-(cis-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carbonyl)-cyclohexyl]-aceticacid ethyl ester; ESI-MS m/z 737 [M+1]+, Retention time 2.35 min(condition A).

The following compounds are prepared following the procedure of Example7

ESI-MS m/z Retention No Product [M + 1]+ time (min) Starting Material 1

641 2.56 (condition A)

2

613 4.90 (condition C)

Example 8 Synthesis of[trans-4-(cis-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carbonyl)-cyclohexyl]-aceticacid ethyl ester

(trans-4-{cis-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2,6-diethylpiperidine-1-carbonyl}-cyclohexyl)-aceticacid ethyl ester (205 mg, 0.419 mmol),1-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(116 mg, 0.419 mmol), tetrakis(triphenylphosphine)palladium(0) (32.2 mg,0.0279 mmol), and sodium carbonate (59.1 mg, 0.558 mmol) are dissolvedin H2O (0.54 ml) and DME (2.7 ml). The mixture is stirred at 95° C. for2 hours and cooled to room temperature. To the mixture is added 1M HClin EtOH (6 mL), and the solution is stirred at room temperature for 2hours. To the mixture is added 4M HCl in dioxane (6 mL), and thesolution is stirred at room temperature for 2 hours. Saturated aqueousNaHCO3 is added to the mixture, and the solution is extracted withdichloromethane. The solvent is removed under reduced pressure, and theobtained residue is purified by silica gel column chromatography to give[trans-4-(cis-4-{(3,5-bis(trifluoromethyl)benzyl)-[5-(1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carbonyl)-cyclohexyl]-aceticacid ethyl ester (140 mg 69.4%); ESI-MS m/z 723 [M+1]+, Retention time2.29 min (condition A).

Example 9cis-4-{(3,5-Bis(trifluoromethyl)benzyl)-[5-((S)-3-hydroxy-pyrrolidin-1-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester

Pd2(dba)3 (10.7 mg, 0.012 mmol) and 2-(di-tert-butylphosphino)biphenyl(7.0 mg, 0.023 mmol) are dissolved in toluene (2 mL). Upon cooling,sodium tert-butoxide (90 mg, 0.940 mmol),(S)-(−)-3-benzoyloxypyrrolidine (0.67 g, 5.5 mmol) andcis-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester (0.52 g, 2.2 mmol) are added, and the reactionmixture is heated at 100° C. for 3 hours. After cooling to roomtemperature, MeOH (4 mL), THF (1 mL) and aqueous 5M NaOH is added, andthe reaction mixture is stirred at room temperature for additional 1hour. After adding saturated aqueous NH4Cl, the mixture is extractedwith EtOAc. The combined organic layer after dried over MgSO4 isconcentrated to obtaincis-4-{(3,5-bis(trifluoromethyl)benzyl)-[5-((S)-3-hydroxy-pyrrolidin-1-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester as colorless oil (110 mg, 73%) after purificationby silica gel column chromatography.

The following compounds are prepared using the same procedure asdescribed in Example 3.

ESI-MS m/z Retention Starting Starting No. Product [M + 1]+ time (min)Material Material 1

646 2.40 (condition A)

trans-cyclohexane- 1,2-diamine instead of dimethylamino-acetic acid 2

659 2.42 (condition A)

trans-cyclohexane- 1,2-diamine instead of dimethylamino-acetic acid

Example 10 Synthesis of(4-{cis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carbonyl}-cyclohexyl)-aceticacid ethyl ester

cis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-6-ethyl-piperidine-1-carboxylicacid tert-butyl ester (900 mg, 1.29 mmol) is dissolved in 4M HCl inAcOEt. The solution is stirred at room temperature for 4 hours thenremoved under reduced pressure. To the obtained residue is added diethylether, and precipitates are filtered and washed with ether. The solid isdried under reduced pressure to give(cis-2-benzyl-6-ethylpiperidin-4-yl)-(3,5-bis(trifluoromethyl)benzyl)-(5-bromo-pyrimidin-2-yl)-aminehydrochloride (771 mg 93.6%); ESI-MS m/z 601 [M+1]+, Retention time 2.14min (condition A).

To a solution of 4-ethoxycarbonylmethyl-cyclohexanecarboxylic acid (83.9mg, 0.392 mmol) in THF 1 mL is added thionyl chloride (143 uL, 1.96mmol). The mixture is stirred at room temperature for 18 hours thenconcentrated under reduced pressure. The obtained residue is added to asolution of(cis-2-benzyl-6-ethylpiperidin-4-yl)-[3,5-bis(trifluoromethyl)benzyl]-(5-bromo-pyrimidin-2-yl)-aminehydrochloride (50 mg, 0.0784 mmol), triethylamine (110 uL, 0.784 mmol)in DMF (2 ml). The mixture is stirred at 150° C. for 1 hour undermicrowave irradiation. The product is purified by reverse-phase HPLC togive(4-{cis-2-benzyl-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromopyrimidin-2-yl)-amino]-6-ethylpiperidine-1-carbonyl}-cyclohexyl)-aceticacid ethyl ester (13 mg, 20.8%); ESI-MS m/z 797 [M+1]+, Retention time2.79 min (condition A).

The following compounds are prepared following the procedure of Example10 using corresponding carboxylic acid.

ESI-MS m/z Retention No Product [M + 1]+ time (min) Starting Material 1

804 2.46 (condition A)

2

735 2.54 (condition A)

Example 11 Synthesis ofcis-4-{(3,5-bis(trifluoromethyl)benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carboxylicacid 3-methoxycarbonyl-propyl ester

cis-4-{(3,5-bis(trifluoromethyl)benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester is dissolved in 4M HCl in AcOEt. The solution isstirred at room temperature for 2 hours and precipitates are collectedby filtration.

To the solid, saturated aqueous NaHCO3 and AcOEt are added, and thesolution is extracted with AcOEt. The organic layer is washed withbrine, dried over MgSO4, and concentrated under reduced pressure to give(3,5-bis(trifluoromethyl)benzyl)-(cis-2,6-diethylpiperidin-4-yl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine(5.0 g, 91%); ESI-MS m/z 541 [M+1]+, retention time 1.84 min (conditionA).

To 4-hydroxy-butyric acid methyl ester (43.7 mg, 0.370 mmol) is added asolution of triphosgene (73.6 mg, 0.248 mmol) in dichloromethane (2 mL)and a solution of pyridine (31.4 uL, 0.388 mL) in dichloromethane (2 mL)sequentially at 0° C. The mixture is stirred at room temperature for 3hours. To the mixture is added saturated aqueous NH4Cl, and the mixtureis extracted with dichloromethane. The solvent is removed under reducedpressure. The obtained residue is added to a solution of(3,5-bis(trifluoromethyl)benzyl)-(cis-2,6-diethylpiperidin-4-yl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine(100 mg, 0.185 mmol) in DMF (100 uL) at room temperature then addeddiisopropylethylamine (60 uL, 0.463 mmol). After stirring at roomtemperature for 15 hours, H2O is added, and the solution is extractedwith dichloromethane. The organic layer is concentrated under reducedpressure, and the residue is purified by silica gel columnchromatography to givecis-4-{(3,5-bis(trifluoromethyl)benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carboxylicacid 3-methoxycarbonylpropyl ester (121 mg, 95.4%); ESI-MS m/z 685[M+1]+, Retention time 2.29 min (condition A).

The following compounds are prepared following the procedure of Example11 using corresponding alcohol.

ESI-MS m/z Retention No. Product [M + 1]+ time (min) 1

699 2.32 (condition A) 2

699 2.34 (condition A) 3

725 2.35 (condition A) 4

725 2.39 (condition A) 5

671 2.25 (condition A) 6

730 2.39 (condition A) 7

723 2.36 (condition A) 8

913 5.26 (condition B) 9

697 2.33 (condition A) 10

713 2.33 (condition A) 11

697 2.36 (condition A) 12

657 5.25 (condition B) 13

738 2.48 (condition A) 14

675 5.26 (condition B) 15

725 2.59 (condition A) 16

711 2.41 (condition A) 17

792 2.51 (condition A) 18

739 2.53 (condition A) 19

730 2.34 (condition A) 20

743 2.36 (condition A) 21

751 2.63 (condition A) Starting Starting No. Material Material 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

Example 12 1) Synthesis of2-ethyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To a solution of 4-methoxypyridine (15.6 g, 143 mmol) in dry THF (1 L)cooled to −35° C. is added ClCO2Ph (22.7 g, 144 mmol). After stirringthe slurry for 1 hour, EtMgBr (150 mL, 150 mmol) is added slowly over 30min. The mixture is warmed to 10° C. over 2 hours then quenched withH2O. The reaction mixture is extracted twice with Et2O (1 L), combinedorganic layer is dried over Na2SO4, and the solvent is removed underreduced pressure. To a solution of the resultant colorless oil in dryTHF (500 mL) at −78° C. is added t-BuOK (64 g, 572 mmol). The reactionmixture is stirred overnight and warmed to room temperature. Thereaction mixture is diluted with Et2O, quenched with ice, partitioned,and the organic layer is washed three times with 1.5 N aqueous NaOH andthen with brine, dried over MgSO4 and concentrated in reduced pressureto afford 2-ethyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester as a pale yellow oil (27.8 g, 86% yield); ESI-MS m/z:226 [M+1]+, Retention time 1.64 min (condition A).

The following material is prepared following the above procedure.

Name Structure Reagent 2-Methyl-4-oxo-3,4- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

MeMgBr instead of EtMgBr 2-Benzyl-4-oxo-3,4- dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

BnMgBr instead of EtMgBr

2) Synthesis of 2,6-diethyl-4-oxo-piperidine-1-carboxylic acidtert-butyl ester

To CuI (0.82 mmol, 156 mg) in a flask purged with N2 is added 1.00 Mtetrahydrofuran solution of EtMgBr (0.82 mmol, 0.82 ml) at −78° C. Afterstirring the suspension for 30 min, BF3.Et2O (0.41 mmol, 57.9 mg) isadded and stirred for 10 min at the same temperature. To the suspensionis added tetrahydrofuran solution (3.3 mL) of2-ethyl-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester(0.41 mmol, 92.7 mg) at −78° C., then the mixture is allowed to stir for1.5 hours and then allow to stir at −40° C. for 2 hours. The mixture iswarmed to room temperature and quenched with saturated aqueous NH4Cl andextracted with EtOAc. The combined organic layers are washed with brine,dried over MgSO4, filtered, concentrated under reduced pressure, andpurified by silica gel column chromatography (eluent: hexane/EtOAc=10/1)and separated the cis and trans isomers of racemic2,6-diethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (50 mg,50%); ESI-MS m/z: 200 [M-tBu+2]+, Retention time 3.51 min. (conditionA).

The following material is prepared following the above procedure.

Name Structure Starting Material 2-Benzyl-6-ethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

2,6-Dimethyl-4-oxo- piperidine-1-carboxylic acid tert-butyl ester

MeMgBr instead of EtMgBr

3) Synthesis ofcis-4-{(5-bromo-pyrimidin-2-yl)[3,5-bis(trifluoromethylbenzyl)]}amino-2,6-diethyl-piperidine-1-carboxylicacid tert-butyl ester

To a mixture of cis-2,6-diethyl-4-oxo-piperidine-1-carboxylic acidtert-butyl ester (11.1 g, 44 mmol) in MeOH (150 mL) is added benzylamine(7.1 mL, 65 mmol) and titanium tetraisopropoxide (26 mL, 87 mmol) at 0°C. The mixture is stirred overnight while warming to room temperature.After addition of sodium tetraborohydride (2.5 g, 65 mmol), the mixtureis stirred for additional 1 hour at room temperature. H2O and EtOAc areadded to the mixture, and the resulting precipitate is removed byfiltration. The filtrate is washed sequentially with saturated aqueousNaHCO3 and brine. The aqueous layer is extracted with EtOAc, and thecombined organic layer after dried over MgSO4 are concentrated to obtaincis-4-benzylamino-2,6-diethyl-piperidine-1-carboxylic acid tert-butylester as clear oil (13.9 g, 92%) after purification. ESI-MS m/z: 346[M+1]+, Retention time 1.80 min (condition A).cis-4-Benzylamino-2,6-diethyl-piperidine-1-carboxylic acid tert-butylester (4.0 g, 11.4 mmol) is dissolved in EtOH (80 mL). In presence of10% Pd/C (400 mg), the reaction mixture is stirred for 5 hours at 55° C.under hydrogen. After removal of the catalyst, solvent is evaporated toobtain cis-4-amino-2,6-diethyl-piperidine-1-carboxylic acid tert-butylester as clear oil (2.9 g, 99%) which is used for next step withoutfurther purification. ESI-MS m/z: 256 [M+1]+, Retention time 1.61 min(condition A).

A mixture of cis-4-amino-2,6-diethyl-piperidine-1-carboxylic acidtert-butyl ester (7.29 mmol, 1.87 g), 5-bromo-2-chloropyrimidine (8.02mmol, 1.55 g), i-Pr2NEt (14.0 mmol, 2.54 mL) and DMF (20 mL) is stirredat 120° C. for 4 hours. After cooling to room temperature, the mixtureis diluted with EtOAc and washed with H2O and brine. The organic layeris dried over Na2SO4 and concentrated. The resulting solid isrecrystallized from i-Pr2O and n-hexane to givecis-4-(5-bromo-pyrimidin-2-ylamino)-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester as white solid; ESI-MS m/z: 414 [M+1]+, Retentiontime 2.29 min. (condition A).

To a solution ofcis-4-(5-bromo-pyrimidin-2-ylamino)-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester (14.6 mmol, 6.05 g) in DMF (60 mL) is added NaH(60% in oil, 17.6 mmol, 0.70 g) at 0° C. After stirring for 1 hour,3,5-bis(trifluoromethyl)benzyl bromide (17.6 mmol, 3.23 mL) is added,and the reaction mixture is warmed to room temperature. After stirringfor 20 minutes, the reaction is quenched with H2O at 0° C. The mixtureis extracted with EtOAc, washed with brine, dried over Na2SO4 andconcentrated. The obtained residue is purified by silica gel columnchromatography to give4-{(5-bromo-pyrimidin-2-yl)[3,5-bis(trifluoromethyl)benzyl]}amino-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester (8.02 g, 86%) as yellow oil; ESI-MS m/z: 639[M+]+,Retention time 6.27 min. (condition B).

ESI-MS m/z Retention Product [M + 1]+ time (min) Starting Material

701 5.84 (Condition B)

611 5.50 (Condition C)

Example 13 Synthesis ofcis-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-tetrazol-1-yl-pyrimidin-2-yl)-amino]-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester

A round-bottom flask is charged with Pd2(dba)3 (17 mg, 0.019 mmol) andBINAP (35 mg, 0.057 mg) and purged with nitrogen. To the flask is added4-[(3,5-bis(trifluoromethyl)benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester (120 mg, 0.19 mmol), benzophenone imine (38 uL,0.23 mmol), sodium tert-butoxide (27 mg, 0.29 mmol) and toluene (2 mL),and the mixture is heated to 110° C. for 3 hours. The mixture is cooledto room temperature, diluted with Et2O, filtered, and concentrated togive brown oil which is used for next step without further purification.

To a solution of the imine adduct in THF (1 mL) is added aqueous 2M HCl(1 mL). After stirred for 30 minutes, the mixture is basified withaqueous 2M NaOH. The mixture is extracted with CH₂Cl₂, dried overanhydrous Na2SO4 and concentrated under reduced pressure. The obtainedresidue is purified silica gel column chromatography to givecis-4-[(5-amino-pyrimidin-2-yl)-(3,5-bis(trifluoromethyl)benzyl)-amino]-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester (69 mg, 0.12 mmol, 60%).

Tocis-4-[(5-amino-pyrimidin-2-yl)-(3,5-bis(trifluoromethyl)benzyl)-amino]-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester in acetic acid (1 mL) is added triethylorthoformate (30 uL, 0.18 mmol) under nitrogen, and the mixture isheated at 75° C. After stirred for 30 min at 75° C., NaN3 (24 mg, 0.21mmol) is added and stirred for 3 hours. The mixture is basified withsaturated NaHCO3 and extracted with EtOAc, dried over Na2SO4, purifiedby silica gel chromatography to give 23 mg (0.06 mmol, 52%)cis-4-[(3,5-bis(trifluoromethyl)benzyl)-(5-tetrazol-1-yl-pyrimidin-2-yl)-amino]-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester.

Example 14 1) Synthesis of2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine

To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) andtriisopropyl borate (12 mmol, 2.8 mL) in toluene (16 mL) and THF (4 mL)is added n-butyl lithium in hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at−78° C. over 45 min and stirred at −78° C. for 1 hour. The mixture iswarmed to −20° C., then added aqueous 1M HCl (20 mL). The mixture iswarmed to room temperature. The precipitate is collected and washed withhexane to give a colorless powder (808 mg, 51%). A mixture of the powder(3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO4 (18.15 mmol,2.2 g) in toluene (10 mL) is stirred at room temperature for 15 hour.The mixture is filtrated and the solution is concentrated under reducedpressure. The resultant solid is washed with water to give2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine(875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol]+, Retention time 1.75 min(condition A).

2) Synthesis ofcis-4-[(5-Benzyloxy-pyrimidin-2-yl)-(3,5-bis(trifluoromethyl)benzyl)-amino]-2,6-diethylpiperidine-1-carboxylicacid 4-methoxycarbonyl-cyclohexyl ester

A solution of 4-amino-2,6-diethylpiperidine-1-carboxylic acid tert-butylester (3.9 mmol, 1 g),2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine(4.7 mmol, 1.1 g) and N,N-diisopropylethylamine (5.9 mmol, 1.1 mL) inDMF (12 ml) is allowed to warm to 120° C. and stirred for 3 hours. Themixture is cooled to room temperature and then water is added. Themixture is extracted with EtOAc. The combined organic layer is driedover Na2SO4, filtrated, and concentrated under reduced pressure.

The obtained residue is dissolved in THF (15 mL) and added aqueous H2O2(35%, 1.14 mL) at room temperature. The mixture is stirred at roomtemperature for 2 hours. The mixture is cooled until 0° C. and quenchedwith saturated aqueous sodium thiosulfate. The mixture is extracted withEtOAc, and the combined organic layer is dried over Na2SO4, filtrated,and concentrated under reduced pressure. The obtained residue ispurified by silica gel column chromatography (eluent: hexane/EtOAc) togive2,6-diethyl-4-(5-hydroxy-pyrimidin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (1.12 g, 83%); ESI-MS m/z: 351 [M+1]+, Retentiontime 1.75 min (condition A).

To a mixture of2,6-diethyl-4-(5-hydroxy-pyrimidin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (1.72 mmol, 580 mg) and potassium carbonate (3.23mmol, 1.12 g) in DMF (12 mL) is added benzylamine (3.53 mmol, 0.42 mL)at room temperature and stirred for 2 hours. Water is added to themixture, and the precipitate is collected and washed with hexane to give4-(5-benzyloxy-pyrimidin-2-ylamino)-2,6-diethylpiperidine-1-carboxylicacid isopropyl ester (1.26 g, 74%) as a colorless solid. To a solutionof4-(5-benzyloxy-pyrimidin-2-ylamino)-2,6-diethylpiperidine-1-carboxylicacid isopropyl ester (2.86 mmol, 1.26 g) in DMF (28 mL) is added sodiumhydride (60% oil suspension, 5.72 mmol, 230 mg) at 0° C. and stirred atroom temperature for 20 min. To the mixture is added1-bromomethyl-3,5-bis(trifluoromethyl)benzene (4.29 mmol, 0.79 mL) at 0°C. and stirred at room temperature for 17 hours. To the mixture is addedsodium hydride (60% oil suspension, 2.86 mmol, 115 mg) and1-bromomethyl-3,5-bis(trifluoromethyl)benzene (2.73 mmol, 0.5 mL) at 0°C. and stirred at room temperature for 5 hours. To the mixture is addedwater, and extracted with EtOAc. The combined organic layer is driedover Na2SO4, filtrated, and concentrated under reduced pressure. Theobtained residue is purified by silica gel column chromatography(eluent: n-hexane/EtOAc) to givecis-4-[(5-benzyloxy-pyrimidin-2-yl)-(3,5-bis(trifluoromethyl)benzyl)-amino]-2,6-diethylpiperidine-1-carboxylicacid 4-methoxycarbonyl-cyclohexyl ester (880 mg, 46%); ESI-MS m/z: 667[M+1]+, Retention time 2.69 min (condition A).

3) Synthesis ofcis-4-[[5-(2-Acetoxy-ethoxy]-pyrimidin-2-yl)-(3,5-bis(trifluoromethyl)benzyl)-amino]-2,6-diethyl-piperidine-1-carboxylicacid trans-4-methoxycarbonyl-cyclohexyl ester

cis-4-[(5-Benzyloxy-pyrimidin-2-yl)-(3,5-bis(trifluoromethyl)benzyl)-amino]-2,6-diethylpiperidine-1-carboxylicacid trans-4-methoxycarbonyl-cyclohexyl ester (0.72 mmol, 540 mg) and10% Pd/C in MeOH is hydrogenated for 30 min. The solution isconcentrated under reduced pressure. The obtained residue is purified bysilica gel column chromatography (eluent: hexane/EtOAc) to givecis-4-[[5-(2-acetoxy-ethoxy)-pyrimidin-2-yl]-(3,5-bis(trifluoromethyl)benzyl)-amino]-2,6-diethylpiperidine-1-carboxylicacid trans-4-methoxycarbonyl-cyclohexyl ester (335 mg, 70%); ESI-MS m/z:661 [M+1]+, Retention time 2.39 min (condition A).

To a mixture ofcis-4-[[5-(2-acetoxy-ethoxy]-pyrimidin-2-yl]-(3,5-bistrifluoromethyl)benzyl)-amino]-2,6-diethylpiperidine-1-carboxylicacid trans-4-methoxycarbonyl-cyclohexyl ester (0.15 mmol, 100 mg),acetic acid 2-hydroxy-ethyl ester (0.225 mmol, 21 uL) andtriphenylphosphine (0.225 mmol, 59 mg) in THF (0.75 mL) is added DEAD(0.225 mmol, 33 uL) at room temperature and then stirred for 15 hours.To the mixture is added water, and extracted with CH2Cl2. The combinedorganic layer is dried over Na2SO4, filtrated, and concentrated underreduced pressure. The obtained residue is purified by silica gel columnchromatography (eluent: hexane/EtOAc) to give4-[[5-(2-acetoxy-ethoxy)-pyrimidin-2-yl]-(3,5-bis(trifluoromethyl)benzyl)-amino]-2,6-diethylpiperidine-1-carboxylicacid trans-4-methoxycarbonyl-cyclohexyl ester (45 mg, 40%); ESI-MS m/z:747 [M+1]+, Retention time 2.54 min (condition A).

Example 15 Synthesis ofcis-4-{[4-(1-Methylpyrazole-4-yl)pyrimidin-2-yl](3,5-dichlorobenzyl)amino}-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester

A mixture ofcis-4-(5-bromo-pyrimidin-2-ylamino)-2,6-diethyl-piperidine-1-carboxylicacid tert-butyl ester (2.42 mmol, 1.00 g), 1-methyl-pyrazole-4-boronicacid pinacol ester (3.14 mmol, 654 mg),tetrakis(triphenylphosphine)palladium (0.242 mmol, 280 mg), sodiumcarbonate (3.63 mmol, 385 mg), H2O (1.9 mL) and DME (10 mL) is stirredunder N2 atmosphere at 90° C. After stirring for 6 hours, the mixture iscooled to room temperature and diluted with EtOAc. The resulting mixtureis washed with H2O and brine, dried over Na2SO4 and concentrated. Theobtained residue is purified by flash silica gel column chromatography(eluent; MeOH/dichloromethane=1/8) and the resulting solid isrecrystallized from i-Pr2O and n-hexane to givecis-2,6-diethyl-4-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-piperidine-1-carboxylicacid tert-butyl ester (793 mg, 79%) as white solid; ESI-MS m/z: 415[M+1]+, Retention time 3.12 min. (condition A).

To a solution of NaH (60% in mineral oil, 0.022 g, 0.55 mmol) in dry DMF(1 mL) cooled to 0° C. is addedcis-4-[4-(1-methylpyrazole-4-yl)pyrimidin-2-yl]-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester (0.15 g, 0.36 mmol). After stirring the resultingsolution at room temperature for 30 minutes, 3,5-dichlorobenzylchloride(0.13 g, 0.54 mmol) is added, and the resulting mixture is stirred for 2hours. The mixture is quenched with 1M HCl, then extracted twice withethyl acetate. The combined organic layer is washed with brine, driedover MgSO4, filtered, concentrated under reduced pressure. The obtainedresidue is purified by silica gel column chromatography to affordcis-4-{[4-(1-methylpyrazole-4-yl)pyrimidin-2-yl](3,5-dichlorobenzyl)amino}-2,6-diethylpiperidine-1-carboxylicacid tert-butyl ester (0.10 g, 48%). 1H-NMR (400 MHz, CDCl3): 0.85 (t,6H), 1.40-1.55 (m, 4H), 1.48 (s, 9H), 1.75-1.83 (m, 2H), 2.10-2.19 (m,2H), 3.95 (s, 3H), 4.07-4.14 (m, 2H), 4.73 (s, 2H), 4.73-4.83 (m, 1H),7.12 (d, 2H), 7.22 (t, 1H), 7.53 (s, 1H), 7.66 (s, 1H), 8.43 (s, 2H).

The following compounds are prepared following the procedure of Example15

ESI-MS m/z Retention NO. Product [M + 1]+ time (min) Starting Material 1

591 2.39 (condition B).

Example 16 Preparation of Alcohol 1) Synthesis of 5-hydroxy-pentanoicacid methyl ester

To a solution of sodium methoxide (71.3 mg, 1.32 mmol) in anhydrous MeOH(4 ml), tetrahydro-pyran-2-one (1.32 g, 13.2 mmol) is added dropwise atroom temperature under nitrogen. The mixture is stirred at 50° C. for 4hours and filtered through a silica gel short column (eluent: diethylether). Collected filtrate is concentrated under reduced pressure togive 5-hydroxy-pentanoic acid methyl ester; 1H NMR (400 MHz,chloroform-d) ppm 1.57-1.76 (m, 4H), 2.35 (m, 2H), 3.65 (m, 5H).

2) Synthesis of cis-4-Hydroxy-cyclohexanecarboxylic acid methyl ester

To a solution of trans-4-hydroxycyclohexanecarboxylic acid (5.0 mmol,721 mg), K2CO3 (15.0 mmol, 2.07 g) in DMF (17 mL) is added iodomethane(6.0 mmol, 0.374 mL). After stirring for 2 h, the mixture is dilutedwith EtOAc. The mixture is washed with H2O and brine, dried over Na2SO4and concentrated. The residue is used to next reaction without furtherpurification (643 mg, 81%); ESI-MS m/z: 159 [M+1]+, Retention time 1.34min. (condition A).

3) Synthesis of trans-4-Hydroxy-cyclohexanecarboxylic acid methyl ester

To a solution of trans-4-hydroxycyclohexanecarboxylic acid (14.7 mmol,2.12 g), K2CO3 (17.6 mmol, 2.44 g) in DMF (15 mL) is added iodomethane(17.6 mmol, 1.10 mL). After stirring for 2 hours, the mixture is dilutedwith EtOAc. The mixture is washed with H2O and brine, dried over Na2SO4and concentrated. The obtained residue is used to next reaction withoutfurther purification (1.62 g, 70%); 1H-NMR (400 MHz, CDCl₃): 1.24-1.33(m, 2H), 1.45-1.53 (m, 2H), 1.98-2.28 (m, 4H), 2.21-2.29 (m, 1H),3.57-3.64 (m, 1H), 3.67 (s, 3H).

4) Synthesis of 5-hydroxy-4,4-dimethyl-pentanoic acid methyl ester

To a solution of 2,2-dimethyl-pentanedioic acid (3.0 g, 19 mmol) isadded K2CO3 (6.49 g, 47 mmol) and iodomethane (2.5 ml, 39 mmol) at roomtemperature. The mixture is stirred at room temperature for 18 hours. Tothe mixture, H2O is added and the solution is extracted with AcOEt. Theorganic layer is washed with H2O, saturated aqueous NaHCO3 and brine,and dried over MgSO4. Solvent is removed under reduced pressure to give2,2-dimethyl-pentanedioic acid dimethyl ester (2.49 g, 70%); TLC(hexane/AcOEt, 3:1) Rf 0.50, 1H NMR (400 MHz, chloroform-d) δ ppm 1.19(s, 6H), 1.88 (m, 2H), 2.29 (m, 2H), 3.67 (s, 6H).

To a solution of 2,2-dimethyl-pentanedioic acid dimethyl ester (2.40 g,12.8 mmol) in MeOH (15 ml) is added potassium hydroxide (0.788 g, 14.0mmol). The mixture is stirred at room temperature for 16 hours andrefluxed for 2 hours. The mixture is cooled to room temperature andconcentrated under reduced pressure. To the obtained residue, 1M aqueousHCl (14 ml) is added and the solution is extracted with ether. Theorganic layer is washed with H2O, dried over Na2SO4, and concentratedunder reduced pressure to give 2,2-dimethyl-pentanedioic acid 1-methylester (1.97 g, 88%); ¹H NMR (400 MHz, chloroform-d) ppm 1.20 (s, 6H),1.87-1.91 (m, 2H), 2.32-2.36 (m, 2H), 3.67 (s, 3H).

To a suspension of 2,2-dimethyl-pentanedioic acid 1-methyl ester (1.00g, 5.75 mmol) in THF (3 mL), 1M LiBHEt3 in THF (38.0 ml, 38.0 mmol) isadded dropwise maintaining the temperature below 10° C. under nitrogen.The mixture is stirred at 10° C. for 1 hour. To the mixture, 50% AcOH(4.6 mL) and H2O are added. The solution is extracted with AcOEt, andthe organic layer is washed with H2O, dried over MgSO4, and concentratedunder reduced pressure to give 5-hydroxy-4,4-dimethyl-pentanoic acid(850 mg, quant.); ¹H NMR (400 MHz, chloroform-d) ppm 1.06 (s, 6H), 1.70(t, 2H), 2.56 (t, 2H), 3.98 (s, 2H).

To a solution of 5-hydroxy-4,4-dimethyl-pentanoic acid (300 mg, 2.05mmol) in DMF (5 ml), K2CO3 (369 mg, 2.87 mmol) and iodomethane (154 ul,2.47 mmol) are added at room temperature. The mixture is stirred at roomtemperature for 15 hours. To the mixture, H2O is added and the solutionis extracted with AcOEt. The organic layer is washed with H2O, andbrine, and dried over MgSO4, and concentrated under reduced pressure.The residue is purified by silica gel column chromatography to give5,5-dimethyl-tetrahydro-pyran-2-one (150 mg, 47%); TLC (hexane/AcOEt,2:1) Rf 0.40, ¹H NMR (400 MHz, chloroform-d) δ ppm 1.06 (s, 6H), 1.70(t, 2H), 2.56 (t, 2H), 3.97 (s, 2H).

To a solution of sodium methoxide (6.32 mg, 0.117 mmol) in anhydrousMeOH (346 mL), 5,5-dimethyl-tetrahydro-pyran-2-one (150 mg, 1.17 mmol)is added dropwise at room temperature under nitrogen. The mixture isstirred at 50° C. for 4 hours and filtered through a silica gel shortcolumn (eluent: diethyl ether). The filtrate is concentrated underreduced pressure to give 5-hydroxy-4,4-dimethyl-pentanoic acid methylester (175 mg, 93%); TLC (hexane/AcOEt, 2:1) Rf 0.27, ¹H NMR (400 MHz,chloroform-d) δ ppm 0.89 (s, 6H), 1.63 (m, 2H), 2.32 (m, 2H), 3.28 (d,2H), 3.68 (s, 3H).

5) Synthesis of trans-3-hydroxy-cyclobutanecarboxylic acid methyl ester

To a solution of cis-trans mixture of 3-hydroxy-cyclobutanecarboxylicacid methyl ester (1.30 g, 10 mmol) in DMF 13 mL, NaH (50% in oil, 720mg, 15 mmol) is added at 0° C. After stirring at 0° C. for 15 minutes,benzyl bromide (1.43 ml, 12 mmol) is added at 0° C. The mixture isstirred at room temperature for 2 hours and quenched with H2O. Thesolution is extracted with AcOEt. The organic layer is washed with H2Oand brine, dried over MgSO4 and concentrated under reduced pressure. Theresidue is purified by silica gel column chromatography to givetrans-3-benzyloxy-cyclobutanecarboxylic acid methyl ester (340 mg,15.4%); TLC (hexane/AcOEt, 5:1) Rf 0.40, ¹H NMR (400 MHz, chloroform-d)

ppm 2.26-2.34 (m, 2H), 2.48-2.52 (m, 2H), 3.02-3.06 (m, 1H), 3.69 (s,3H), 4.26-4.33 (m, 1H), 4.42 (s, 2H), 7.27-7.35 (m, 5H).

A solution of trans-3-benzyloxy-cyclobutanecarboxylic acid methyl ester(680 mg, 3.09 mmol) as a 0.05 M solution in MeOH is pumped through theH-Cube™ flow hydrogenator fitted with a 10 mol % Pd/C catalyst cartridgeheated to 40° C. at 10 bar. The flow rate is set at 1 ml/min. Thesolvent is removed under reduced pressure to give trans3-hydroxy-cyclobutanecarboxylic acid methyl ester (380 mg, 94.5%); TLC(hexane/AcOEt, 1:1) Rf 0.38, 1H NMR (400 MHz, chloroform-d) δ ppm2.18-2.25 (m, 2H), 2.55-2.61 (m, 2H), 3.01-3.08 (m, 1H), 3.70 (s, 3H),4.53-4.61 (m, 1H).

6) Synthesis of cis-4-Hydroxymethyl-cyclohexanecarboxylic acid methylester

To a slurry of NaH (440 mg, 11 mmol) in THF (22 mL) is addedtrans-1,4-cyclohexanedimethanol (1.44 g, 10 mmol) at 0° C., and themixture is stirred for 1 hour while warming to room temperature. Benzylbromide (1.2 mL, 10 mmol) is added dropwise followed by TBAI (185 mg,0.5 mmol). The reaction is heated to 60° C. for 15 hours. After coolingto room temperature, H2O is added, and the mixture is extracted withEtOAc. The combined organic layer after dried over MgSO4 is concentratedto obtain (4-benzyloxymethyl-cyclohexyl)-methanol as clear oil (1.40 g,60%) after purification.

To a mixture of (4-benzyloxymethyl-cyclohexyl)-methanol (1.40 g, 6 mmol)in dichloromethane 28 mL is added Dess-Martin periodinate (2.53 g, 6mmol) at 0° C., and the mixture is stirred for 0.5 hour while warming toroom temperature. After addition of saturated aqueous NaHCO3, themixture is extracted with EtOAc. The combined organic layer after driedover MgSO4 is concentrated to obtain4-benzyloxymethyl-cyclohexanecarbaldehyde as clear oil (1.07 g, 79%)after purification.

4-Benzyloxymethyl-cyclohexanecarbaldehyde (1.70 g, 2.0 mmol) isdissolved in acetic acid (0.24 mL) and 2 mL of methanol. The reactionmixture is cooled to 0° C. to 5° C. and stirred while 10% NaOCl solution(2.5 mL, 4 mmol) is added dropwise over 20 minutes. The cooling bath isremoved, and the mixture is allowed to come to room temperature. Afteraddition of saturated aqueous NaHCO3, the mixture is extracted withEtOAc. The combined organic layer after dried over MgSO4 is concentratedto obtain 4-benzyloxymethyl-cyclohexanecarboxylic acid methyl ester asclear oil (343 mg, 65%) after purification.

4-Benzyloxymethyl-cyclohexanecarboxylic acid methyl ester (340 mg, 1.30mmol) is dissolved in MeOH (15 mL). In presence of catalytic amount of10% Pd/C, the reaction mixture is stirred for 3 hours under hydrogen (10bar). After removing 10% Pd/C, solvent is evaporated to obtaintrans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester ascolorless oil (160 mg, 72%) after purification. 1H-NMR (400 MHz, CDCl3),δ (ppm): 0.99 (m, 2H), 1.47 (m, 3H), 1.88 (m, 2H), 2.02 (m, 2H), 2.23(m, 1H), 3.46 (d, 2H), 3.66 (s, 3H).

7) Synthesis of 1-Hydroxymethyl-cyclopentanecarboxylic acid methyl ester

To a solution of malonic acid dimethyl ester (5.28 g, 40 mmol) in DMF(100 ml), 1,4-dibromo-butane (5.26 ml, 44 mmol), K2CO3 (13.8 g, 100mmol), 1-butyl-3-methylimidazolium tetrafluoroborate (0.904 g, 4.0 mmol)are added at room temperature. The mixture is stirred at roomtemperature for 15 hours. To the mixture, water is added and thesolution is extracted with AcOEt. The organic layer is washed with H2Oand brine, dried over MgSO4, and concentrated under reduced pressure.The residue is purified by silica gel column chromatography to givecyclopentane-1,1-dicarboxylic acid dimethyl ester (6.13 g, 82%); TLC(hexane/AcOEt, 5:1) Rf 0.48, ¹H NMR (400 MHz, chloroform-d) δ ppm1.67-1.71 (m, 4H), 2.17-2.21 (m, 4H), 3.72 (s, 6H).

To a solution of cyclopentane-1,1-dicarboxylic acid dimethyl ester (4.0g, 21.5 mmol) in MeOH (25 mL) is added potassium hydroxide (1.32 g, 23.7mmol). The mixture is stirred at room temperature for 15 hours andconcentrated under reduced pressure. To the obtained residue, aqueous 1MHCl (50 mL) is added and the solution is extracted with AcOEt. Theorganic layer is washed with H2O, dried over Na2SO4, and concentratedunder reduced pressure to give cyclopentane-1,1-dicarboxylic acid methylester (3.72 g, quant.); TLC (dichloromethane/MeOH, 10:1) Rf 0.25, ¹H NMR(400 MHz, chloroform-d) δ ppm 1.67-1.74 (m, 4H), 2.17-2.25 (m, 4H), 3.75(s, 3H).

To a solution of cyclopentane-1,1-dicarboxylic acid methyl ester (1.00g, 5.81 mmol) and triethylamine (808 uL, 5.81 mmol) in THF (15 mL) isadded isobutyl chloroformate (750 uL, 5.81 mmol) at 0° C. The mixture isstirred at 0° C. for 20 minutes. The mixture is filtrated, and thefiltrate is added to a suspension of NaBH4 (242 mg) in THF (15 ml) at 0°C. The mixture is stirred at 0° C. for 3 hours and at room temperaturefor 12 hours. To the mixture, H2O is added and the mixture is extractedwith AcOEt. The organic layer is dried over MgSO4, and concentratedunder reduced pressure. The obtained residue is purified by silica gelcolumn chromatography to give 1-hydroxymethyl-cyclopentanecarboxylicacid methyl ester (433 mg, 47%); TLC (hexane/AcOEt, 1:1) Rf 0.43, ¹H NMR(400 MHz, chloroform-d) δ ppm 1.61-1.77 (m, 6H), 1.93-2.00 (m, 2H), 2.53(m, 1H), 3.57 (d, 2H), 3.72 (s, 3H).

8) Synthesis of trans-(3-hydroxy-cyclobutyl)-acetic acid methyl ester

To a mixture of but-3-enoic acid methyl ester (1.00 g, 10 mmol) andzinc-copper couple (1.97 g) in 1,2-dimethoxyethane (4.89 ml) and diethylether (37 ml), trichloroacetyl chloride (2.98 ml, 26.7 mmol) is added atroom temperature under nitrogen. The mixture is stirred at roomtemperature for 3 days. The mixture is filtrated and washed with diethylether. The filtrate is concentrated under reduced pressure, and theobtained residue is purified by silica gel column chromatography to give(2,2-dichloro-3-oxo-cyclobutyl)-acetic acid methyl ester (2.93 g,quant.); TLC (hexane/AcOEt, 3:1) Rf 0.35, ¹H NMR (400 MHz, chloroform-d)δ ppm 2.68-2.74 (m, 1H), 2.94-3.00 (m, 1H), 3.06-3.13 (m, 1H), 3.33-3.41(m, 1H), 3.51-3.57 (m, 1H), 3.75 (s, 3H).

To a solution of (2,2-dichloro-3-oxo-cyclobutyl)-acetic acid methylester (2.93 g, 13.8 mmol) in AcOH (100 ml), zinc powder (4.51 g, 69.0mmol) is added. The mixture is stirred at 100° C. for 15 hours. Themixture is filtrated and washed with AcOH. The filtrate is concentratedunder reduced pressure, and the residue is dissolved in AcOEt, andwashed with saturated aqueous NaHCO3 and brine. The organic layer isdried over MgSO4, and concentrated under reduced pressure to give(3-oxo-cyclobutyl)-acetic acid methyl ester (710 mg, 36%); 1H NMR (400MHz, chloroform-d) δ ppm 2.64-2.66 (m, 2H), 2.78-2.86 (m, 3H), 3.22-3.32(m, 2H), 3.70 (s, 3H).

To a solution of (3-oxo-cyclobutyl)-acetic acid methyl ester (700 mg,4.92 mmol) in MeOH (20 ml), NaBH4 (205 mg, 5.41 mmol) is added at 0° C.The mixture is stirred at room temperature for 5 hours. To the mixture,H2O is added and a portion of MeOH is removed under reduced pressure.The mixture is extracted with AcOEt and the organic layer is dried overMgSO4, and concentrated under reduced pressure. The obtained residue ispurified by silica gel column chromatography to give cis(3-hydroxy-cyclobutyl)-acetic acid methyl ester (578 mg, 80%); TLC(hexane/AcOEt, 1:1) Rf 0.38, 1H NMR (400 MHz, chloroform-d) δ ppm1.56-1.65 (m, 1H), 1.76 (m, 1H), 2.08-2.16 (m, 2H), 2.44 (d, 2H),2.51-2.59 (m, 2H), 3.66 (s, 3H), 4.16 (m, 1H).

To a solution of cis-(3-hydroxy-cyclobutyl)-acetic acid methyl ester(570 mg, 3.96 mmol), triphenylphosphine (2.08 g, 7.92 mmol), and4-nitrobenzoic acid (1.32 g, 7.92 mmol) in dry THF (50 mL), 40% diethylazodicarboxylate in toluene (1.42 mL, 7.92 mmol) is added at roomtemperature. The mixture is stirred at room temperature for 15 hours.The solvent is removed under reduced pressure, and the obtained residueis purified by silica gel column chromatography to givetrans-4-nitro-benzoic acid 3-methoxycarbonylmethyl-cyclobutyl ester (558mg, 48%); TLC (hexane/AcOEt, 3:1) Rf 0.31, 1H NMR (400 MHz,chloroform-d) δ ppm 2.28-2.35 (m, 2H), 2.44-2.51 (m, 2H), 2.56 (d, 2H),2.82-2.87 (m, 1H), 3.69 (s, 3H), 5.33-5.40 (m, 1H). 8.18-8.30 (m, 4H).

To a solution of trans-4-nitro-benzoic acid3-methoxycarbonylmethyl-cyclobutyl ester (540 mg, 1.84 mmol) in MeOH (20mL) is added H2O (2.4 mL), THF (10 mL), and K2CO3 (255 mg, 1.84 mmol) atroom temperature. The mixture is stirred at room temperature for 45minutes. The solvent is removed under reduced pressure. Water is addedto the obtained residue, and the mixture is extracted withdichloromethane. The organic layer is concentrated under reducedpressure then purified by silica gel column chromatography to givetrans-(3-hydroxy-cyclobutyl)-acetic acid methyl ester (230 mg, 87%); TLC(hexane/AcOEt, 1:1) Rf 0.40, 1H NMR (400 MHz, chloroform-d) δ ppm1.69-1.70 (m, 1H), 2.07-2.19 (m, 4H), 2.44-2.46 (d, 2H), 2.41-2.69 (m,1H), 3.66 (s, 3H), 4.39-4.47 (m, 1H).

9) Synthesis of trans-2-(3-hydroxy-cyclobutyl)-2-methyl-propionic acidmethyl ester

To a solution trans-(3-hydroxy-cyclobutyl)-acetic acid methyl ester (168mg, 1.17 mmol) in DMF (1.5 mL) is added, NaH (60% in oil, 70 mg, 1.75mmol) at 0° C. After stirring at 0° C. for 15 minutes, benzyl bromide(167 uL, 1.40 mmol) is added at 0° C. The mixture is stirred at roomtemperature for 2 hours and quenched with H2O. The mixture is extractedwith dichloromethane, and the organic layer is concentrated underreduced pressure. The obtained residue is purified by silica gel columnchromatography to give trans-(3-benzyloxy-cyclobutyl)-acetic acid methylester (110 mg, 40%); ESI-MS m/z 235 [M+1]+, retention time 1.97 min(condition A).

To a solution of trans-(3-benzyloxy-cyclobutyl)-acetic acid methyl ester(110 mg, 0.47 mmol) in THF (1 mL) is added 1.09M LDA in THF and hexane(1.51 mL, 1.65 mmol) at −78° C. under nitrogen, and stirred at −78° C.for 30 min. To the mixture, iodomethane (232 ul, 3.76 mmol) is added,and the mixture is stirred at −78° C. for 30 min. The temperature isslowly warmed to room temperature for 3 hours. To the mixture, H2O isadded and extracted with AcOEt. The organic layer is dried over MgSO4and concentrated under reduced pressure to givetrans-2-(3-benzyloxy-cyclobutyl)-propionic acid methyl ester (94 mg,80%); ESI-MS m/z 249 [M+1]+, retention time 2.07 min (condition A).

To a solution of trans-2-(3-benzyloxy-cyclobutyl)-propionic acid methylester (94 mg, 0.38 mmol) in THF (1 mL) is added 1.09M LDA in THF andhexane (1.51 mL, 1.65 mmol) at −78° C. under nitrogen, and stirred at−78° C. for 30 minutes. To the mixture, iodomethane (232 uL, 3.76 mmol)is added, and stirred at −78° C. for 30 minutes. The temperature isslowly warmed to room temperature for 3 hours. To the mixture, H2O isadded and extracted with AcOEt. The organic layer is dried over MgSO4and concentrated under reduced pressure to givetrans-2-(3-benzyloxy-cyclobutyl)-2-methyl-propionic acid methyl ester(70 mg, 70%); ESI-MS m/z 263 [M+1]+, retention time 2.17 min (conditionA).

A solution of trans-2-(3-benzyloxy-cyclobutyl)-2-methyl-propionic acidmethyl ester (70 mg, 0.26 mmol) as 0.05 M solution in MeOH is pumpedthrough the H-Cube™ flow hydrogenator fitted with 10 mol % Pd/C catalystcartridge heated to 40° C. at 10 bar. The flow rate is set at 1 mL/min.The solvent is removed under reduced pressure to givetrans-2-(3-hydroxy-cyclobutyl)-2-methyl-propionic acid methyl ester (54mg, quant.); TLC (hexane/AcOEt, 1:1) Rf 0.45, 1H NMR (400 MHz,chloroform-d) δ ppm 1.12 (s, 6H), 1.92-2.03 (m, 2H), 2.18-2.24 (m, 2H),2.63-2.71 (m, 1H), 3.65 (s, 3H), 4.25-4.31 (m, 1H).

10) Synthesis of 4-Hydroxy-butyric acid methyl ester

To a solution of sodium methoxide (71.3 mg, 1.32 mmol) in anhydrous MeOH(4 mL) dihydro-furan-2-one (1.14 g, 13.2 mmol) is added dropwise at roomtemperature under nitrogen. The mixture is stirred at 50° C. for 4 hoursand filtered through a silica gel short column (eluent: diethyl ether).The filtrate is concentrated under reduced pressure to give4-hydroxy-butyric acid methyl ester; ¹H NMR (400 MHz, chloroform-d). δppm 1.85-1.92 (m, 2H), 2.45 (t, 2H), 3.69 (m, 5H).

Example 17 1) Synthesis ofcis-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-mino}-2,6-diethyl-piperidine-1-carboxylicacid 1-tert-butoxycarbonyl-azetidin-3-yl ester

A mixture of 4-hydroxyazetidine hydrochloride (4.66 mmol, 510 mg), Boc2O(5.12 mmol, 1.12 g), saturated aqueous NaHCO3 solution (5 mL) and1,4-dioxane (5 mL) is stirred at room temperature for 1.5 hours. Themixture is diluted with EtOAc, washed with H2O and brine, dried overNa2SO4 and concentrated. To a solution of the obtained residue in CH2Cl2(10 mL) is added pyridine (2.35 mmol, 0.19 mL) and triphosgene (1.12mmol, 332 mg) at 0° C. The mixture is warmed to room temperature andstirred for 1 hour. After cooling to 0° C., the reaction is quenchedwith saturated aqueous NH4Cl solution. The resulting mixture isextracted with CH2Cl2, washed with brine, dried over Na2SO4 andconcentrated. A mixture of the crude material (0.403 mmol, 95 mg),cis-2,6-diethyl-piperidin-4-yl)-[3,5-bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine(0.202 mmol, 109 mg), i-Pr2NEt (1.61 mmol, 0.28 mL) is dissolved in DMF(0.5 mL). After stirring for 0.5 hours, the additional crude material(0.170 mmol, 40 mg) is added. The reaction mixture is diluted withEtOAc, washed with H2O and brine, dried over Na2SO4 and concentrated.The obtained residue is purified by silica gel column chromatography togivecis-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethyl-piperidine-1-carboxylicacid 1-tert-butoxycarbonyl-azetidin-3-yl ester (94 mg, 63%); 1H-NMR (400MHz, CDCl3): 0.86 (t, 6H), 1.45 (s, 9H), 1.45-1.62 (m, 4H), 1.76-1.84(sept, 2H), 2.13-2.21 (m, 2H), 3.90 (dd, 2H), 3.95 (s, 3H), 4.13-4.21(m, 2H), 4.23-4.28 (m, 2H), 4.76-4.84 (m, 1H), 4.87 (s, 2H), 5.11-5.14(m, 1H), 7.53 (s, 1H), 7.66 (d, 1H), 7.70 (s, 1H), 7.75 (s, 1H), 8.44(s, 2H).

2) Synthesis ofcis-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carboxylicacid 1-methoxycarbonylmethyl-azetidin-3-yl ester

To a solution ofcis-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethyl-piperidine-1-carboxylicacid 1-tert-butoxycarbonyl-azetidin-3-yl ester (0.0578 mmol, 37 mg) andi-Pr2NEt (0.116 mmol, 0.020 mL) in THF (1 mL) is added methylbromoacetate (0.0867 mmol, 0.0082 mL). The reaction mixture is graduallywarmed to 60° C. After stirring for 0.5 hours, the reaction mixture isdiluted with EtOAc, washed with H2O and brine, dried over Na2SO4, andconcentrated. The obtained residue is purified by silica gel columnchromatography to givecis-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carboxylicacid 1-methoxycarbonylmethyl-azetidin-3-yl ester (22 mg, 54%) ascolorless oil; ESI-MS m/z: 712 [M+1]+, Retention time 1.95 min.(condition A).

Example 18 Synthesis of (S)-(−)-3-benzoyloxypyrrolidine

To a mixture of N-benzyl-3-hydroxypyrrolidine (0.50 g, 2.84 mmol) indichloromethane (5 mL) and pyridine (0.46 mL, 5.68 mmol) is addedbenzoyl chloride (0.4 mL, 3.41 mmol) at 0° C., and the mixture isstirred for 1 hour while warming to room temperature. After addition ofsaturated aqueous NaHCO3, the mixture is extracted with EtOAc. Thecombined organic layer is dried over MgSO4, filtered, and concentrated.The resulting N-benzyl-3-benzoyloxypyrrolidine is used for next stepwithout further purification.

To a crude mixture of N-benzyl-3-benzoyloxypyrrolidine (114 mg, 0.41mmol) in dichloromethane (1 mL) is added α-chloroethyl chloroformate (57μL, 0.49 mmol) at 0° C., and the mixture is stirred for 1 hour whilewarming to room temperature. After removing dichloromethane, resultingmixture is diluted with MeOH. The reaction mixture is heated to 80° C.for 0.5 hour. After cooling to room temperature, solvent is evaporatedunder reduced pressure to obtain (S)-(−)-3-benzoyloxypyrrolidine whichis used for next reaction without further purification.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A compound of formula (I)

wherein: R1 is heteroaryl, wherein said heteroaryl is optionallysubstituted with one to three substituents selected from halogen,dialkylamino, alkoxy, heterocyclyl, wherein said heterocyclyl is furtheroptionally substituted with one to three substituents selected fromalkyl, hydroxy or alkanoyl, R2 is alkyl; R3 is HOC(O)—R9—O—C(O)—; R4 isalkyl or aryl-alkyl- optionally substituted by one to three alkyl orhalogen; R5 is hydrogen; R6 and R7 are independently halogen, alkyl oralkoxy, wherein said alkyl is optionally substituted with one to threehalogen; and R9 is (C1-C4) alkyl, (C3-C6) cycloalkyl, (C1-C4)alkyl-C3-6cycloalkyl or (C3-C6) cycloalkyl-alkyl; or a pharmaceuticallyacceptable salt thereof, or an optical isomer thereof; or a mixture ofoptical isomers thereof.
 2. The compound according to claim 1, whereinin formula (I) R1 is 5 or 6-membered heteroaryl, wherein said heteroarylis optionally substituted with one to three substituents selected fromhalogen, dialkylamino, (C1-C7) alkoxy, or 5- or 6-membered heterocyclyl,wherein said heterocyclyl is further optionally substituted with one tothree substituents selected from (C1-4)alkyl, (C1-C7)alkanoyl orhydroxy; R2 is (C1-C7) alkyl; R4 is (C1-C7) alkyl or 6-membered arylalkyl, wherein aryl is optionally substituted by one to threesubstituents selected from alkyl or halogen; R5 is hydrogen; R6 and R7are independently halogen, (C1-C7) alkyl or (C1-C7) alkoxy, wherein saidalkyl is substituted with one to three halogens; and R9 is

 —CH₂C(CH₃)₂CH₂CH₂—,

or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition, comprising: a therapeutically effective amount of acompound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarriers.
 4. The pharmaceutical composition according to claim 3,further comprising one or more therapeutically active agents selectedfrom the group consisting of a: (i) HMG-Co-A reductase inhibitor or apharmaceutically acceptable salt thereof, (ii) angiotensin II receptorantagonist or a pharmaceutically acceptable salt thereof, (ii)angiotensin converting enzyme (ACE) Inhibitor or a pharmaceuticallyacceptable salt thereof, (iv) calcium channel blocker or apharmaceutically acceptable salt thereof, (v) aldosterone synthaseinhibitor or a pharmaceutically acceptable salt thereof, (vi)aldosterone antagonist or a pharmaceutically acceptable salt thereof,(vii) dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP)inhibitor or a pharmaceutically acceptable salt thereof, (viii)endothelin antagonist or a pharmaceutically acceptable salt thereof,(ix) renin inhibitor or a pharmaceutically acceptable salt thereof, (x)diuretic or a pharmaceutically acceptable salt thereof, and (xi) anApoA-I mimic.
 5. A compound according to claim 1 selected from:

or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition, comprising: a therapeutically effective amount of acompound of formula (I) according to claim 5, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarriers.